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Article

Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions

by
Zhanhui Yang
,
Hassane Abdellaoui
,
Wei He
and
Jiaxi Xu
*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(5), 784; https://doi.org/10.3390/molecules22050784
Submission received: 6 February 2017 / Revised: 8 May 2017 / Accepted: 9 May 2017 / Published: 12 May 2017
(This article belongs to the Collection Heterocyclic Compounds)
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Versions Notes

Abstract

:
The ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with linear imines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, the sulfa-Staudinger cycloadditions deliver cis-β-sultams in considerable amounts, together with the predominant trans-β-sultams. In other cases, the above sulfa-Staudinger cycloadditions give rise to trans-β-sultams exclusively. Further mechanistic rationalization discloses that the ortho-nitro effect is attributed to its strong electron-withdrawing inductive effect. Similarly, the ortho-nitro effect also exists in Staudinger cycloadditions of ethoxycarbonyl ketene with the imines. The current research provides further insights into the diastereoselective control in sulfa-Staudinger and Staudinger cycloadditions.

Graphical Abstract

1. Introduction

Recently, β-sultams have received much attention in both synthetic and medicinal chemistry [1,2,3,4,5,6,7,8], mainly because of their outstanding biological activities as, for example, antibiotics and enzyme inhibitors [9,10,11,12,13]. As a result, many synthetic methods to β-sultams have been developed [14,15,16,17]. Among them, the most promising is the sulfa-Staudinger cycloaddition [18,19,20,21,22,23,24], which is referred to as the [2s + 2i] annulation between sulfenes (or their equivalents) with imines, because of the rich and diverse sources of the starting materials.
In our previous work, we successfully disclosed the stepwise mechanism of the sulfa-Staudinger cycloaddition [25,26], and the substituent-controlled annuloselectivity [27,28] and diastereoselectivity [29] in the cycloaddition. The previous studies on the diastereoselectivity revealed that the [2s + 2i] annulation of the active ethoxycarbonylmethanesulfonyl chloride (1a) and ethyl malonyl chloride (1b) with various linear imines 2 gave trans-β-sultams 3 or trans-β-lactams 4 exclusively, regardless of the imine substituents (Scheme 1) [27,28,29,30,31]. However, in our continuing studies, we further found that when C-2-nitroaryl imines 2 were applied in the reactions, besides trans-β-sultams 3, cis-β-sultams 5 were generated in considerable amounts (Scheme 1, X = SO2). This unexpected phenomenon is, herein, considered as the ortho-nitro effect. Moreover, such ortho-nitro effect also was observed in the Staudinger ketene-imine cycloadditions (Scheme 1, X = CO).
Previous work on the nitro effect mainly focused on the reactivity of certain compounds [32,33,34], mainly because of the electronic properties of the nitro group. In addition, the shielding effect of the nitro group was also reported [35]. However, the nitro effect on the diastereoselectivity has not been reported until now. Herein, we rationalize how the ortho-nitro effect works to generate cis-β-sultams and cis-β-lactams in the reactions of C-2-nitroaryl imines with sulfenes and ketenes, respectively, and hope that the current research could help to further understand the diastereoselective control in the sulfa-Staudinger and Staudinger cycloadditions.

2. Results and Discussion

2.1. Experimental Studies on the Ortho-Nitro Effect in Controlling Cis-Selectivity of Sulfa-Staudinger Cycloadditions

Previously, the ortho-nitro effect was seldom observed in our studies on the substituent-controlled annuloselectivity [27,28]. The reaction between sulfonyl chloride 1a and C-2-nitrophenylimine 2a gave rise to a mixture of trans- and cis-β-sultams 3a and 5a in 66% total isolated yield, with an 82:18 trans/cis ratio (Table 1, entry 1) [36]. However, C-3- and 4-nitrophenyl imines 2b and 2c afforded the corresponding trans-β-sultams 3b and 3c exclusively in 79% and 41% isolated yields, respectively, in the reactions with the same sulfonyl chloride 1a (Table 1, entries 2 and 3). The sulfa-Staudinger reactions of other C-2-nitrophenyl imines 2d–f with sulfonyl chloride 1a produced the corresponding cis-β-sultams 5d–f as well, with trans/cis ratios 86:14, 88:12, and 97:3, respectively (Table 1, entries 4–6). The increasing trend of the trans/cis ratios from entry 4 to entry 6 is in good accordance to our previous diastereoselective guidelines, that is, the bulky N-substituents of imines favor the trans-selectivity [29]. These results indicate that the generation of cis-β-sultams in the sulfa-Staudinger reactions of C-2-nitrophenyl imines with ethoxycarbonylmethanesulfonyl chloride (1a) is a general and regular phenomenon. In these reactions, the ortho-nitro group on the C-aryl group plays an important role in formation of cis-β-sultams. Experimental results from entries 7–9 in Table 1 present a decreasing trend of the trans/cis ratios without obvious difference between C-2-nitrophenylimine 2a and C-3- and 4-nitrophenylimines 2b and 2c, revealing that the ortho-nitro effect does not exist in the sulfa-Staudinger cycloadditions involving other alkanesulfonyl chlorides, such as phenylmethanesulfonyl chloride (1c). In the presence of weak bases such as pyridine, the ortho-nitro effect still exists (Table 1, entries 10–12). In addition, [2 + 2 + 2] cycloadducts 7 were observed in low yields when excessive N-methyl imines were employed (Table 1, entries 2 and 3), while [4 + 2] annuladducts 8, generated from enolate-sulfene and imines, were not observed in any cases. It is noteworthy that the trans/cis ratios do not change upon storage for several months or treatment with imines for several days, indicating that the reactions are under kinetic control.
To distinguish whether other ortho-substituents affect the diastereoselectivity, other imines derived from ortho-substituted aromatic aldehydes were also tested in the reactions of sulfonyl chloride 1a. As shown in entries 2–9 in Table 2, regardless of the ortho-substituents of imines 2g–o, all the sulfa-Staudinger annuladducts trans-3g–o were generated in excellent diastereoselectivities, with the trans/cis ratios varying from 97:3 to 100:0. All the above results indicate that only when a nitro group is present at the ortho-position in the C-aryl groups of imines 2 would cis-β-sultams be generated in considerable amounts. The other 2-substituents at the aryl groups of imines scarcely affect the diastereoselectivities, as demonstrated by reactions of imines 2g–o (Table 2, entries 2–10). However, the presence of an additional electron-withdrawing group, such as 4-NO2 and 5-MeO (according to Hammett constants, meta-MeO is an electron-withdrawing group), at the 2-nitroaryl promoted the formation of the corresponding cis-products, as shown in entries 11 and 12 of Table 2.

2.2. Rationale on the Ortho-Nitro Effect in Controlling Cis-Selectivity of Sulfa-Staudinger Cycloadditions

One question of significant concern is how the ortho-nitro effect controls the formation of cis-β-sultams together with trans-β-sultams. Before answering this question, the mechanism in sulfa-Staudinger reactions should first be introduced. In our previous report [25,26,27,28,29], the mechanism for the formation of β-sultam rings has been rationalized. Under thermal conditions, the imines exist in E-configuration, as demonstrated by our previous work [37]. As depicted in Scheme 2, arylmethane- or alkane-sulfonyl chlorides 1 (R1 = aryl or alkyl) first sulfonylate imines 2 to afford intermediates A, which further generate intermediates C or their resonation forms D through elimination of a proton by a weak base or imines. Alternatively, sulfenes B, generated from electron-deficient sulfonyl chlorides 1 (R1 = CO2Et) such as ethoxycarbonylmethanesulfonyl chloride (1a) in the presence of weakly basic imines 2 [27,28,29], react with nucleophilic imines 2 to deliver intermediates C or their resonation forms D. Direct conrotation of D gives rise to cis-β-sultams 5, while isomerization of D into E, followed by conrotation of E produces trans-β-sultams 3. The isomerization step is realized by a C–N bond rotation through G and F as possible intermediates. The diastereoselectivity (cis/trans-selectivity) is virtually the competitive results between the direct conrotation and isomerization of zwitterionic 2,3-thiaza-1,3-butadiene-type intermediates D. The electron-withdrawing substituents of sulfenes decrease the rate (kd) of the direct conrotatory ring closure of zwitterionic intermediates D, resulting in favorable formation of trans-β-sultams 3, while the electron-withdrawing C-substituents of imines increase the rate of the direct conrotatory ring closure, leading to predominant formation of cis-β-sultams 5.
Szymonifka and Heck also studied the reactions of methoxycarbonylsufene with imines, and trans-β-sultams were formed exclusively [19]. They proposed zwitterionic enolate-iminium intermediates H (eqn. 1, Scheme 3). As demonstrated by Tsuge and Iwanami’s results [38], if enolate-iminium intermediates H are formed, the more favorable six-membered products 2,3-dihydro-1,4,3-oxathiazine 4,4-dioxides 8 should be generated (eqn. 2, Scheme 3). However, the fact is that 2,3-dihydro-1,4,3-oxathiazine 4,4-dioxide products 8 were not observed in either Szymonifka’s [19] or our studies (eqn. 1, Scheme 3) [27,28,29]. Therefore, it is not enolate-iminium intermediates H but sulfenolate-iminium intermediates D or E that partake in the ring closure step in the ester-stabilized systems. The results are in accordance with the general observation that acylacetate esters are predominantly enolized rather than malonate diesters.
The reaction of sulfonyl chloride 1a and C-2-nitrophenylimine 2a shows higher cis-selectivity (trans/cis ratio of 82:18) than those in reactions of 1a with C-3- and 4-nitrophenyl imines 2b and 2c (Table 1, entries 1–3). Additionally, all reactions of C-2-nitrophenylimines 2d–f increase cis-selectivities compared with reactions of other C-2-substituted phenyl imines 2g–o (Table 1, entries 4–6 vs. Table 2, entries 2–9). Thus, in reactions of C-2-nitrophenylimines, the formation of cis-β-sultams 5 can be attributed to the strong electron-withdrawing inductive effect of the ortho-nitro group rather than steric hindrance. Both C-3- and 4-nitrophenyl imines 2b and 2c afforded the corresponding trans-β-sultams 3b and 3c exclusively in the reactions with the same sulfonyl chloride 1a (Table 1, entries 2 and 3) due to longer distances from the nitro group to the carbon atom of the iminium than that in the ortho-nitro substrate, weakening the electron-withdrawing inductive effect because the inductive effect exerts electron-withdrawing influence through the carbon chain and decreases along with distance. The results also reveal that the conjugation effect of the nitro group does not play an important role in controlling the cis-selectivity because the conjugation effect is not closely related to the distance.
To further verify the influence of the inductive effect of the nitro group on the diastereoselectivity, imine 2p with C-2,4-dinitrophenyl group and imine 2q with C-5-methoxy-2-nitrophenyl group were reacted with sulfonyl chloride 1a; the corresponding cis-β-sultams 5p and 5q increased obviously compared with that from C-2-nitrophenylimine 2a. The results indicate that the ortho-nitro effect on the cis-selectivity is its strong electron-withdrawing inductive effect.
On the other hand, the increase of cis-β-sultams 5 may also be obtained by decelerating the isomerization of D to E (Scheme 2). One significantly important factor in affecting the isomerization is the steric hindrance of R2. The isomerization is realized by the C–N bond rotation (from F to G). If R2 is sterically too large, the C–N conrotation will not overcome the steric hindrance between R1 and R2, and the isomerization will be decelerated or prevented, promoting the generation of cis-β-sultams 5, even as sole products in some cases. This phenomenon was observed in the reactions of phenylmethanesulfonyl chlorides with (E)-1-(anthracen-9-yl)-N-benzylmethanimine, which bore a sterically very large 9-anthracenyl group (R2), and only cis-β-sultam was obtained in our previous work [29]. Imines 2g−o in entries 2–9 in Table 2 have sterically approximate or larger groups than the nitro group at their 2-positions. However, cis-β-sultams 5 were generated in trace amounts. The comparison indicates that it is not the steric interaction between the ortho-nitroaryl group (R2) and the ethoxycarbonyl group that leads to cis-β-sultams 5. Actually, as illustrated in Scheme 2, during the isomerization of D to E, the C–N bond rotation in intermediates F could occur clockwise or anticlockwise, following the direction with the least steric hindrance. In other words, the steric interaction between the ortho-substituents and CO2Et cannot decelerate the isomerization, and this is the reason why the reactions of a variety of 2-substituted imines with 1a predominantly give trans-β-sultams 3 (Table 2, entries 2–10). The steric interaction between the ortho-nitroaryl group (R1) and the ethoxycarbonyl group (R2) is not the key factor that leads to the ortho-nitro effect.
Additionally, the electrostatic interaction between the ortho-nitro group and the ethoxycarbonyl group is possibly another factor for the ortho-nitro effect as shown in (Figure 1); the positively charged nitrogen atom of the nitro group interacts with the partially negatively charged oxygen atom of the C=O bond in the ethoxycarbonyl group, to some extent stabilizing the intermediates D′ and decelerating the isomerization of D′ to E′. As a consequence, cis-β-sultams 5 were generated. Thus, the electrostatic interaction is another rationale for the ortho-nitro effect in the current sulfa-Staudinger cycloadditions. Such an electrostatic interaction does not exist between the 3-nitro or 4-nitro group and the ethoxycarbonyl group possibly because of the far distance between them. Consequently, the corresponding cis-β-sultams 5b or 5c were not generated (Table 1, entries 2 and 3). However, on the basis of the results from imines 2p and 2q, the electrostatic interaction between the ortho-nitro group and the ethoxycarbonyl group is not a major factor for the ortho-nitro effect even if it exists.

2.3. Ortho-Nitro Effect in the Staudinger Ketene-Imine Cycloadditions

To examine the generality of the ortho-nitro effect, the Staudinger cycloadditions of ethyl malonyl chloride (1b) and some C-nitroaryl imines 2 were conducted. The ortho-nitro effect was also observed in Staudinger ketene-imine cycloadditions. The results were summarized in Table 3. Ethoxycarbonylketene, generated from ethyl malonyl choride (1b) in the presence of 2-chloropyridine, smoothly reacted with C-2-nitrophenyl imine 2d, giving rise to both trans-4d and cis-6d with a trans/cis ratio as 83:17 (Table 3, entry 1) [36]. However, the reactions of C-3-nitrophenyl and C-4-nitrophenyl imines 2p and 2q delivered trans-β-lactams 4p and 4q exclusively in 54%, and 58% yields, respectively (Table 3, entries 2 and 3). The ortho-nitro effect in the Staudinger ketene-imine cycloaddition is a common phenomenon, and is affected by the N-substituents of C-2-nitroaryl imines. For example, the reactions of N-methyl imine 2a and N-benzyl imine 2e afforded the trans/cis ratios in 85:15 and 81:19, respectively (Table 3, entries 4 and 5). However, the reaction of N-tert-butyl imine 2f produced more cis-β-lactam 6f with a 64:36 trans/cis ratio (Table 3, entry 6) possibly due to the Thorpe-Ingold effect [39,40]. Correspondingly, imine 2r reacted with acyl chloride 1b, only giving trans-β-lactam 4r in 74% yield (Table 3, entry 7).
The ortho-nitro effect exists in not only sulfa-Staudinger sulfene-imine cycloadditions, but also Staudinger ketene-imine cycloadditions, to some extent indicating that the structures of the two zwitterionic intermediates D and I involved in the above two types of cycloadditions are similar [37,41,42,43,44,45,46,47,48] (Figure 2). The nature of the ortho-nitro effect in Staudinger cycloadditions is the same as that in sulfa-Staudinger cycloadditions.

3. Materials and Methods

3.1. Materials and Instruments

Tetrahydrofuran was dried by refluxing over sodium with diphenyl ketone as an indicator. Melting points were obtained on a Yanaco MP-500 melting point apparatus (Yanaco Ltd., Osaka, Japan) and are uncorrected. 1H- and 13C-NMR spectra were recorded on a Bruker AM 400 MHz spectrometer (Bruker Company, Billerica, MA, USA) in CDCl3 with TMS as an internal standard and the chemical shifts (δ) are reported in parts per million (ppm). The IR spectra (KBr pellets) were taken on a Nicolet FTIR 920 spectrometer (Thermo Nicolet Corporation, Madison, WI, USA). HRMS measurements were carried out on an Agilent LC/MSD TOF mass spectrometer (Agilent, Santa Clara, CA, USA). TLC separations were performed on silica gel GF254 plates (Qingdao Ocean Chemical Industry, Qingdao, China), and the plates were visualized with UV light. Column chromatography was performed on silica gel zcx II (200–300 mesh) (Qingdao Ocean Chemical Industry, Qingdao, China) with petroleum-ether (PE) and ethyl-acetate (EA) (Beijing Chemical Reagent Company, Beijing, China) as the eluent.

3.2. General Procedure for the Sulfa-Staudinger Cycloadditions of Sulfonyl Chlorides 1a,c and Imines 2

To a solution of imine 2 (1 mmol) in dry THF (2 mL) was added a solution of sulfonyl chloride 1a (or 1c) (0.5 mmol) in dry THF (0.5 mL) for 0.5 min at room temperature. The mixture was then allowed to stand at room temperature for 24 h, followed by dilution with ether (10 mL), washing with brine (10 mL), and drying over Na2SO4. Filtrating off the desiccant and removing the solvents under vacuum gave rise to a residue, which subsequently was subjected to column chromatography on silica gel with a mixture of petroleum ether (PE, 30–60 °C) and ethyl acetate (EA) as eluent to give the desired β-sultam products.
For the reactions in entries 10–12 in Table 1, the following procedure was used. To a solution of imine 2a or 2b or 2c (22 mg, 0.125 mmol) and pyridine (12 mg, 0.15 mmol) in dry THF (0.5 mL) was added a solution of sulfonyl chloride 1a (28 mg, 0.15 mmol) in dry THF (0.25 mL) for 0.5 min at room temperature. Then the mixture was allowed to stand at room temperature for 24 h, followed by dilution with ether (5 mL), and washing with brine (5 mL). Removing the solvents under vacuum gave rise to a residue, which subsequently was subjected to NMR analysis to determine the trans/cis ratios and yields.
Ethyl trans-2-methyl-3-(2-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3a) [27,28]: Compounds trans-3a and cis-5a were isolated as a mixture, with a trans/cis ratio as 82:18. Yellow oil. Total yield 66% (103 mg). 1H-NMR (400 MHz, CDCl3): 8.11–8.08 (m, 1H), 7.83–7.79 (m, 1H), 7.63–7.59 (m, 1H), 5.02 (d, J = 5.0 Hz, 1H), 4.87 (d, J = 5.0 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.90 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C-NMR (400 MHz, CDCl3): 162.3, 148.3, 134.7, 131.7, 130.1, 129.6, 128.3, 125.4, 80.8, 63.3, 51.6, 31.8, 14.0.
Ethyl cis-2-methyl-3-(2-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (5a) [27,28]: Yellowish oil. 1H-NMR (400 MHz, CDCl3): 8.23 (dd, J = 8.2, 1.1 Hz, 1H), 8.02 (d, J = 7.4 Hz, 1 H), 7.83–7.79 (m, 1H), 7.63–7.59 (m, 1H), 5.67 (d, J = 8.4 Hz, 1H), 4.94 (d, J = 8.4 Hz, 1H), 4.08–3.97 (m, 2H), 2.87 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). 13C-NMR (400 MHz, CDCl3): 161.5, 147.7, 134.4, 133.4, 129.65, 129.64, 125.5, 76.9, 62.5, 53.1, 29.7, 13.7.
Ethyl trans-2-methyl-3-(3-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3b): Known compound [27,28]. Colorless crystals. M.p.: 105–107 °C. Yield 79% (124 mg). 1H-NMR (400 MHz, CDCl3): 8.37 (t, J = 1.8 Hz, 1H), 8.26 (ddd, J = 8.2, 2.1, 0.9 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 4.88 (d, J = 6.6 Hz, 1H), 4.61 (d, J = 6.6 Hz, 1H), 4.44−4.37 (m, 1H), 4.37−4.28 (m, 1H), 2.81 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 13C NMR (400 MHz, CDCl3): 161.8, 148.8, 137.6, 132.6, 130.5, 124.3, 121.7, 79.2, 63.5, 54.5, 31.4, 14.0.
Ethyl trans-2-methyl-3-(4-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3c): Known compound. Colorless oil. Yield 41% (69 mg). 1H-NMR (400 MHz, CDCl3): 8.29 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 4.85 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 1H), 4.40 (dq, J = 10.8, 7.1 Hz, 1H), 4.33 (dq, J = 10.8, 7.1 Hz, 1H), 2.80 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C-NMR (400 MHz, CDCl3): 161.8, 148.5, 142.3, 127.6, 124.5, 79.2, 63.5, 54.5, 31.4, 14.0.
Ethyl trans-3-(2-nitrophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3d): Compounds trans-3d and cis-5d were isolated as a mixture, with a trans/cis ratio as 86:14, from a 1mmol-scale reaction. Yellow oil, total yield 66% (225 mg). 1H-NMR (400 MHz, CDCl3): 8.15 (d, J = 7.8 Hz, 1H), 8.06 (dd, J = 8.2, 0.9 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.61–7.55 (m, 1H), 5.07 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 4.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.44–3.31 (m, 1H), 3.01–2.90 (m, 1H), 1.68–1.57 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.3, 134.4, 132.4, 130.0, 128.5, 125.2, 80.4, 63.3, 50.1, 49.1, 21.6, 14.0, 11.6. IR (KBr): ν 2968, 2938, 2872, 1745, 1533, 1367, 1338, 1258, 1184, 1001, 1011, 861, 793, 518 cm−1. HRMS (ESI) calcd for C14H18N2NaO6S [M + Na]+: 365.0778; found: 365.0771.
Ethyl cis-3-(2-nitrophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (5d): Yellow oil. 1H-NMR (400 MHz, CDCl3): 8.20 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.62–7.54 (m, 1H), 5.62 (d, J = 8.5 Hz, 1H), 4.95 (d, J = 8.5 Hz, 1H), 4.10–4.02 (m, 1H), 4.02–3.94 (m, 1H), 3.43–3.32 (m, 1H), 2.84–2.74 (m, 1H), 1.82–1.71 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.4, 148.3, 134.2, 129.9, 129.6, 125.4, 76.3, 62.5, 51.6, 49.5, 21.8, 13.7, 11.7. IR (KBr): ν 2968, 2938, 2872, 1745, 1533, 1367, 1338, 1258, 1184, 1001, 1011, 861, 793, 518 cm−1. HRMS (ESI) calcd for C14H18N2NaO6S [M + Na]+: 365.0778; found: 365.0771.
Ethyl trans-2-benzyl-3-(2-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3e): Compounds trans-3e and cis-5e were isolated as a mixture, with a trans/cis ratio as 88:12, from a 1-mmol-scale reaction. Yellow oil, total yield 71% (276 mg). 1H-NMR (400 MHz, CDCl3): 8.04 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.56–7.46 (m, 1H), 7.32–7.22 (m, 5H), 5.13 (d, J = 4.8 Hz, 1H), 4.84 (d, J = 4.8 Hz, 1H), 4.53 (d, J = 14.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.25 (d, J = 14.2 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.2, 148.0, 134.2, 133.4, 131.9, 129.8, 128.9, 128.7, 128.7, 128.3, 125.0, 80.4, 63.3, 50.7, 49.8, 14.0. IR (KBr): ν 2987, 2920, 2846, 1735, 1610, 1533, 1453, 1370, 1348, 1181, 1030, 858, 742, 508 cm−1. HRMS (ESI) calcd for C18H18N2NaO6S [M + Na]+: 413.0778; found: 413.0774.
Ethyl cis-2-benzyl-3-(2-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (5e): Yellow oil, 1H-NMR (400 MHz, CDCl3): 8.15 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.56–7.46 (m, 1H), 7.39–7.32 (m, 5H), 5.65 (d, J = 8.6 Hz, 1H), 5.04 (d, J = 8.6 Hz, 1H), 4.53 (d, J = 14.2 Hz, 1H), 4.13 (d, J = 14.3 Hz, 1H), 4.09–4.01 (m, 1H), 4.02–3.92 (m, 1H), 1.07 (t, J = 7.1 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.1, 148.1, 134.0, 130.1, 129.8, 129.5, 128.9, 128.7, 128.7, 128.4, 125.2, 76.4, 62.4, 51.4, 51.0, 13.7. IR (KBr): ν 2987, 2920, 2846, 1735, 1610, 1533,1453, 1370, 1348, 1181, 1030, 858, 742, 508 cm−1. HRMS (ESI) calcd for C18H18N2NaO6S [M + Na]+: 413.0778; found: 413.0774.
Ethyl trans-2-(tert-butyl)-3-(2-nitrophenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3f): Compounds trans-3f and cis-5f were isolated as a mixture, with a trans/cis ratio as 97:3, from a 1-mmol-scale reaction. Only the characteristic data of trans-3f are given. Colorless crystals, yield 65% (231 mg). M.p.: 145–150 °C, 1H-NMR (400 MHz, CDCl3): 8.25 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.59–7.52 (m, 1H), 5.35 (d, J = 3.6 Hz, 1H), 4.65 (d, J = 2.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (s, 9H). 13C-NMR (101 MHz, CDCl3): 162.1, 148.0, 134.1, 129.7, 128.7, 124.8, 80.3, 63.1, 57.8, 45.1, 29.6, 27.7, 13.9, 0.9. IR (KBr): ν 2965, 2923, 1738, 1533, 1455, 1332, 1267, 1178, 1162, 1069, 742, 707 cm−1. HRMS (ESI) calcd for C15H20N2NaO6S [M + Na]+: 379.0934; found: 379.0930.
Trans- and Cis-2-methyl-3-(2-nitrophenyl)-4-phenyl-1,2-thiazetidine 1,1-dioxides (3ac and 5ac): These two compounds were isolated as a mixture, with a trans/cis ratio as 52:48, from a 1-mmol-scale reaction. Since it was difficult to distinguish their 13C-NMR data. The analytical data are summarized together. Colorless crystals. M.p.: 118–125 °C. Yield 15% (47 mg). For trans-3ac, 1H-NMR (400 MHz, CDCl3): 8.19 (d, J = 8.0 Hz, 1H), 7.82–7.78 (m, 1H), 7.57–7.52 (m, 1H), 7.46 (s, 5H), 7.42–7.38 (m, 1H), 5.19 (d, J = 6.4 Hz, 1H), 5.04 (d, J = 6.4 Hz, 1H), 2.84 (s, 3H). For cis-5ac, 1H-NMR (400 MHz, CDCl3): 8.00–7.91 (m, 3H), 7.74–7.68 (m, 1H), 7.17–7.05 (m, 5H), 6.09 (d, J = 8.6 Hz, 1H), 5.27 (d, J = 8.6 Hz, 1H), 2.96 (s, 3H). 13C NMR (101 MHz, CDCl3): 144.5, 144.4, 134.4, 134.1, 131.8, 130.4, 130.0, 129.8, 129.44, 129.38, 129.29, 129.1, 128.9, 128.1, 128.0, 127.9, 127.43, 127.35, 125.7, 125.0, 84.5, 81.1, 57.7, 55.7, 32.1, 30.9. IR (KBr): ν 3070, 2920, 2337, 1524, 1447, 1351, 1322, 1168, 726, 508 cm−1. HRMS (ESI) calcd for C15H14N2NaO4S [M + Na]+: 341.0566; found 341.0563.
Trans-2-methyl-3-(3-nitrophenyl)-4-phenyl-1,2-thiazetidine 1,1-dioxide (3bc): Compounds 3bc and 5bc were isolated from a 1-mmol-scale reaction. Colorless crystals. M.p.: 118–125 °C. Yield: 15% (47 mg). 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 8.25–8.21 (m, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.46 (s, 5H), 5.20 (d, J = 7.2 Hz, 1H), 4.36 (d, J = 7.2 Hz, 1H), 2.85 (s, 4H). 13C-NMR (101 MHz, CDCl3): 148.8, 138.0, 132.4, 130.4, 130.2, 129.3, 129.2, 127.6, 124.2, 121.6, 83.5, 60.3, 30.9. IR (KBr): ν 3070, 2920, 2337, 1524, 1447, 1351, 1322, 1168, 726, 508 cm−1. HRMS (ESI) calcd for C15H14N2NaO4S [M + Na]+: 341.0566; found 341.0563.
Cis-2-methyl-3-(3-nitrophenyl)-4-phenyl-1,2-thiazetidine 1,1-dioxide (5bc): Colorless crystals. M.p.: 154–160 °C. Yield 15% (48 mg) 1H-NMR (400 MHz, CDCl3): 8.06–7.96 (m, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.41–7.34 (m, 1H), 7.21–7.11 (m, 5H), 5.81 (d, J = 8.7 Hz, 1H), 4.81 (d, J = 8.6 Hz, 1H), 2.96 (s, 3H). 13C-NMR (101 MHz, CDCl3): 148.2, 135.9, 133.1, 129.9, 129.5, 129.3, 128.5, 127.5, 123.2, 122.2, 80.8, 58.0, 31.7. IR (KBr): ν 3070, 2920, 2337, 1524, 1447, 1351, 1322, 1168, 726, 508 cm−1. HRMS (ESI) calcd for C15H14N2NaO4S [M + Na]+: 341.0566; found 341.0563.
Cis-2-methyl-3-(4-nitrophenyl)-4-phenyl-1,2-thiazetidine 1,1-dioxide (5cc): Known compound [29]. Colorless crystals. M.p.: 182–183 °C. 1H-NMR (400 MHz, CDCl3): 8.20–7.10 (m, 9H, ArH), 5.83 (d, J = 8.8 Hz, 1H), 4.82 (d, J = 8.8 Hz, 1H), 2.96 (s, 3H).
Trans-2-methyl-3-(4-nitrophenyl)-4-phenyl-1,2-thiazetidine 1,1-dioxide (3cc): Known compound [29]. Colorless crystals. M.p.: 168–169 °C, 1H-NMR (400 MHz, CDCl3): 8.39–7.43 (m, 9H, ArH), 5.18 (d, J = 7.2 Hz, 1H), 4.37 (d, J = 7.2 Hz, 1H), 2.86 (s, 3H).
Ethyl trans-2-propyl-3-(O-Tolyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3g): Compounds trans-3g and cis-5g were isolated as a mixture, with a trans/cis ratio as 99:1, from a 1-mmol-scale reaction. Only the characteristic data of trans-3g are given. Colorless oil, yield 55% (171 mg). 1H-NMR (400 MHz, CDCl3): 7.72 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 6.9 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 4.82 (d, J = 6.3 Hz, 1H), 4.76 (d, J = 6.3 Hz, 1H), 4.40–4.32 (m, 1H), 4.32–4.25 (m, 1H), 3.33–3.20 (m, 1H), 2.86–2.75 (m, 1H), 2.41 (s, 3H), 1.66–1.52 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.4, 136.5, 134.2, 130.9, 128.8, 127.0, 126.0, 79.1, 63.1, 50.5, 48.5, 21.6, 19.2, 14.0, 11.6. IR (KBr): ν 2965, 2930, 2869, 1741, 1469, 1380, 1332, 1242, 1197, 1155, 1014, 752, 701 cm−1. HRMS (ESI) calcd for C15H22NO4S [M + H]+: 312.1264; found: 312.1256.
Ethyl trans-2-propyl-3-(2-(trifluoromethyl)phenyl)-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3h): Compounds trans-3h and cis-5h were isolated as a mixture, with a trans/cis ratio as 97:3, from a 1-mmol-scale reaction. Only the characteristic data of trans-3h are given. Colorless oil, yield: 37% (135 mg). 1H-NMR (400 MHz, CDCl3): 8.09 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 5.04 (d, J = 5.2 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.40–4.33 (m, 1H), 4.33–4.26 (m, 1H), 3.36–3.23 (m, 1H), 2.96–2.82 (m, 1H), 1.62–1.48 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 161.6, 135.43 (q, J = 1.2 Hz), 133.0, 129.1, 128.75 (q, J = 30.8 Hz), 128.2, 126.05 (q, J = 5.8 Hz, 1H), 123.72 (q, J = 273.9 Hz), 80.3, 63.1, 49.2 (q, J = 2.3 Hz), 48.3, 21.4, 13.9, 11.5. IR (KBr): ν 2974, 2929, 1747, 1453, 1312, 1267, 1164, 1119, 1036, 774 cm−1. HRMS (ESI) calcd for C15H19F3NO4S [M + H]+: 366.0981; found: 366.0977.
Ethyl trans-3-(2-methoxyphenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3i): Compounds trans-3i and cis-5i were isolated as a mixture, with a trans/cis ratio as 99:1, from a 1-mmol-scale reaction. Only the characteristic data of trans-3i are given. Colorless oil, yield 78% (255 mg). 1H-NMR (400 MHz, CDCl3): 7.55 (d, J = 7.6 Hz, 1H), 7.38–7.30 (m, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 6.1 Hz, 1H), 4.81 (d, J = 6.0 Hz, 1H), 4.41–4.33 (m, 1H), 4.34–4.25 (m, 1H), 3.81 (s, 3H), 3.38–3.25 (m, 1H), 2.91–2.80 (m, 1H), 1.75–1.55 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.4, 157.1, 130.0, 126.8, 124.5, 120.9, 110.6, 78.1, 62.6, 55.3, 49.14, 49.00, 21.7, 14.1, 11.6. IR (KBr): ν 2968, 2927, 2875, 1748, 1604, 1492, 1335, 1245, 1191, 1024, 755, 710 cm−1. HRMS (ESI) calcd for C15H22NO5S [M + H]+: 328.1213; found: 328.1206.
Ethyl trans-3-(2fluorophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3j): Compounds was isolated from a 0.25-mmol-scale reaction. Pale yellow oil. Yield: 36% (27 mg). 1H-NMR (400 MHz, CDCl3) δ 7.68 (td, J = 7.6, 1.6 Hz, 1H), 7.43–7.35 (m, 1H), 7.30–7.23 (m, 1H), 7.16–7.07 (m, 1H), 4.91 (s, 2H), 4.47–4.27 (m, 2H), 3.37–3.25 (m, 1H), 2.93–2.80 (m, 1H), 1.71–1.54 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3) δ 161.9, 160.79 (d, J = 249.1 Hz), 130.81 (d, J = 8.2 Hz), 127.79 (d, J = 3.1 Hz), 124.92 (d, J = 3.7 Hz), 123.35 (d, J = 12.4 Hz), 115.93 (d, J = 20.9 Hz), 78.2, 63.11, 48.7, 47.83, 47.80, 21.5, 14.0, 11.5. IR (KBr): ν 2968, 2935, 2875, 1745, 1491, 1458, 1372, 1338, 1237, 1191, 1159, 1100, 1015, 763 cm−1. HRMS (ESI) calcd for C14H18FNNaO4S [M + Na]+ 338.0833, found 338.0839.
Ethyl trans-3-(2-chlorophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3k): Compounds trans-3j and cis-5j were isolated as a mixture, with a trans/cis ratio as 97:3, from a 1-mmol-scale reaction. Only the characteristic data of trans-3j are given. Colorless crystals, yield 68% (225 mg), M.p.: 51–59 °C. 1H-NMR (400 MHz, CDCl3): 7.78 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 8.2 Hz, 2H), 7.35–7.29 (m, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.77 (d, J =5.6 Hz, 1H), 4.41–4.35 (m, 1H), 4.34–4.28 (m, 1H), 3.41–3.28 (m, 1H), 2.96–2.79 (m, 1H), 1.73–1.53 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.0, 134.2, 133.3, 130.2, 130.0, 127.68, 127.66, 78.9, 63.1, 50.4, 48.9, 21.6, 14.0, 11.6. IR (KBr): ν 2962, 2933, 2869, 1741, 1475, 1469, 1341, 1187, 1040, 755, 701, 518 cm−1. HRMS (ESI) calcd for C14H19ClNO4S [M + H]+: 332.0718; found: 332.0713.
Ethyl trans-3-(2-bromophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3l): Compounds trans-3k and cis-5k were isolated as a mixture, with a trans/cis ratio as 97:3, from a 1-mmol-scale reaction. Only the characteristic data of trans-3k are given. Colorless crystals, yield: 70% (262 mg), M.p.: 76–81 °C. 1H-NMR (400 MHz, CDCl3): 7.82–7.77 (m, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 11.5, 5.0 Hz, 1H), 5.04 (d, J = 5.5 Hz, 1H), 4.75 (d, J = 5.5 Hz, 1H), 4.42–4.35 (m, 1H), 4.35–4.27 (m, 1H), 3.40–3.26 (m, 1H), 2.97–2.83 (m, 1H), 1.70–1.52 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.0, 135.9, 133.3, 130.5, 128.3, 128.0, 123.0, 79.2, 63.1, 52.6, 48.7, 21.5, 14.0, 11.5; IR (KBr): ν 2968, 2933, 2872, 1738, 1469, 1370, 1332, 1261, 1184, 1030, 758, 518 cm−1. HRMS (ESI) calcd for C14H19BrNO4S [M + H]+: 376.0213; found: 376.0204.
Ethyl trans-3-(2,6-dichlorophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3m): Compounds trans-3l and cis-5l were isolated as a mixture, with a trans/cis ratio as 99:1, from a 1-mmol-scale reaction. Only the characteristic data of trans-3l are given. Colorless crystals, yield 53% (193 mg), M.p.: 116–122 °C. 1H-NMR (400 MHz, CDCl3): 7.39 (d, J = 7.8 Hz, 2H), 7.30–7.24 (m, 1H), 5.82 (d, J = 7.1 Hz, 1H), 5.52 (d, J = 7.1 Hz, 1H), 4.40–4.34 (m, 1H), 4.32–4.25 (m, 1H), 3.32–3.25 (m, 1H), 2.81–2.74 (m, 1H), 1.54–1.41 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.3, 136.8, 130.8, 130.01, 129.96, 128.2, 128.1, 73.9, 63.1, 50.7, 48.9, 21.3, 14.0, 11.5. IR (KBr): ν 2971, 2939, 2879, 1738, 1565, 1434, 1389, 1344, 1261, 1194, 1155, 1091, 1011, 774, 518 cm−1. HRMS (ESI) calcd for C14H17Cl2NNaO4S [M + Na]+: 388.0148; found: 388.0371.
Ethyl trans-3-([1,1′-biphenyl]-2-yl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3n): Only compound trans-3m was isolated from a 1-mmol-scale reaction, and the characteristic data are given as following. Yellow oil, yield: 258 mg (69%). 1H-NMR (400 MHz, CDCl3): 7.85 (d, J = 7.8 Hz, 1H), 7.49 (dd, J = 11.0, 4.2 Hz, 1H), 7.45–7.36 (m, 4H), 7.25–7.17 (m, 3H), 4.82 (d, J = 5.8 Hz, 1H), 4.71 (d, J = 5.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.21–3.05 (m, 1H), 2.78–2.71 (m, 1H), 1.55–1.42 (m, 2H), 1.23 (t, J = 7.1 Hz, 4H), 0.88 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 161.6, 142.7, 139.4, 133.9, 130.3, 129.3, 128.6, 128.5, 128.4, 127.7, 126.4, 79.6, 62.8, 50.3, 48.0, 21.5, 13.9, 11.5. IR (KBr): ν 2962, 2933, 2869, 1735, 1601, 1482, 1364, 1332, 1258, 1191, 1001, 1011, 861, 752, 697, 521 cm−1. HRMS (ESI) calcd for C20H24NO4S [M + H]+: 374.1421; found: 374.1430.
Ethyl trans-3-(naphthalen-2-Yl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3o): Only compound trans-3n was isolated, and the characteristic data are given as following. Colorless crystals. Yield: 147 mg (85%). M.p: 114–118 °C. 1H-NMR (400 MHz, CDCl3): 7.96 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89–7.82 (m, 2H), 7.65 (dd, J = 8.5, 1.7 Hz, 1H), 7.58–7.49 (m, 2H), 4.90 (d, J = 6.4 Hz, 1H), 4.72 (d, J = 6.4 Hz, 1H), 4.42–4.33 (m, 1H), 4.33–4.25 (m, 1H), 3.28 (ddd, J = 12.9, 8.2, 7.1 Hz, 1H), 2.86 (ddd, J = 12.9, 8.2, 7.1 Hz, 1H), 1.68–1.52 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 162.3, 133.6, 133.2, 133.1, 129.4, 128.0, 127.8, 126.84, 126.83, 126.6, 123.4, 79.0, 63.1, 54.4, 48.4, 21.6, 14.0, 11.6. IR (KBr): ν 2969, 2920, 2870, 1735, 1469, 1332, 1194, 1162, 1024, 819, 745, 473 cm−1. HRMS (ESI) calcd for C18H22NO4S [M + H]+: 348.1264; found 348.1274.
Ethyl trans-3-(2,4-dinitrophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3p): Compounds trans-3o and cis-5o were isolated as a mixture, with a trans/cis ratio as 75:25, from a 1-mmol-scale reaction. Yellow oil, total yield 60% (232 mg). 1H-NMR (400 MHz, CDCl3): 8.89 (s, 1H), 8.61 (d, J = 7.3 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H), 5.14 (d, J = 4.6 Hz, 1H), 4.84 (d, J = 4.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.49–3.35 (m, 1H), 3.05–2.89 (m, 1H), 1.63 (dq, J = 14.7, 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 161.8, 148.3, 148.2, 138.9, 130.6, 128.4, 120.7, 80.4, 63.6, 63.0, 50.0, 49.5, 21.6, 14.0, 11.5; IR (KBr): ν 2965, 2933, 2872, 1741, 1607, 1540, 1466, 1348, 1258, 1184, 1002, 1009, 835, 796 cm−1. HRMS (ESI) calcd for C14H18N3O8S [M + H]+: 388.0809; found: 388.0802.
Ethyl cis-3-(2,4-dinitrophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (5p): 1H-NMR (400 MHz, CDCl3): 9.02 (s, 1H), 8.61 (d, J = 7.3 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 5.71 (d, J = 8.6 Hz, 1H), 4.99 (d, J = 8.6 Hz, 1H), 4.17–4.08 (m, 1H), 4.09–3.99 (m, 1H), 3.49–3.36 (m, 1H), 2.86–2.75 (m, 1H), 1.81–1.69 (m, 2H), 1.19 (t, J = 7.1 Hz,3H), 1.06 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 161.4, 147.9, 147.7, 137.9, 131.7, 127.9, 120.7, 76.5, 63.6, 51.3, 49.8, 21.8, 13.8, 11.6. IR (KBr): ν 2965, 2933, 2872, 1741, 1607, 1540, 1466, 1348, 1258, 1184, 1002, 1009, 835, 796 cm−1. HRMS (ESI) calcd for C14H18N3O8S [M + H]+: 388.0809; found: 388.0802.
Ethyl trans-3-(5-methoxy-2-nitrophenyl)-2-propyl-1,2-thiazetidine-4-carboxylate 1,1-dioxide (3q): Compounds trans-3q and cis-5q were isolated as a mixture, with a trans/cis ratio as 85:15, from a 0.25-mmol-scale reaction. Colorless oil. Yield: 68% (63 mg).
NMR data for the trans-isomer: 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.01 (dd, J = 9.1, 2.8 Hz, 1H), 5.16 (d, J = 4.5 Hz, 1H), 4.78 (d, J = 4.5 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.52–3.39 (m, 1H), 3.06–2.94 (m, 1H), 1.73–1.59 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 164.5, 162.5, 140.6, 135.8, 128.4, 114.4, 113.5, 80.5, 63.2, 56.1, 50.7, 49.3, 21.7, 14.0, 11.6.
NMR data for the cis-isomer: 1H-NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.1 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.01 (dd, J = 9.1, 2.8 Hz, 1H), 5.65 (d, J = 8.6 Hz, 1H), 5.00 (d, J = 8.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.47–3.36 (m, 1H), 2.82 (dt, J = 12.7, 7.9 Hz, 1H), 1.83–1.72 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H). 13C-NMR (101 MHz, CDCl3): 164.2, 161.4, 133.9, 128.3, 114.8, 114.4, 114.0, 76.1, 62.3, 56.1, 51.9, 49.6, 21.9, 13.7, 11.7.
IR (KBr): ν 2968, 2939, 2875, 1747, 1612, 1581, 1517, 1484, 1466, 1370, 1340, 1288, 1240, 1230, 1182, 1085, 1033, 860, 848, 828, 754 cm−1. HRMS (ESI) calcd for C15H20N2NaO7S [M + Na]+: 395.0883; found: 395.0885.

3.3. General Procedure for the Staudinger Cycloadditions of Ethyl Malonyl Chloride (1b)

To a solution of imine 2 (0.5 mmol) and 2-chloropyridne (113 μL, 1.2 mmol) in dry THF (3 mL) was dropwise added a solution of ethyl malonyl chloride (1b) (0.181 g, 1.2 mmol) in dry THF (2 mL) via a syringe for 3 min. Upon addition, the resulting mixture was allowed to stir at room temperature for 12 h. Then ether (15 mL) and brine (10 mL) were added sequentially. After washing, the organic phase was dried over MgSO4. Removal of the solvent and purification on silica gel chromatography afforded the desired corresponding products trans-4 and cis-6.
Ethyl trans-4-(2-nitrophenyl)-1-propylazetidin-2-one-3-carboxylate (4d): Compounds trans-4d and cis-6d were isolated as a mixture, with a trans/cis ratio as 90:10. Yellowish oil. Yield 43% (65 mg). 1H-NMR (400 MHz, CDCl3): 8.14–8.08 (m, 1H), 7.77–7.71 (m, 1H), 7.60–7.52 (m, 2H), 5.31 (d, J = 2.3 Hz, 1H), 4.40–4.33 (m, 1H), 4.33–4.26 (m, 1H), 3.79 (d, J = 2.2 Hz, 1H), 3.72–3.61 (m, 1H), 2.96–2.88 (m, 1H), 1.69–1.57 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.6, 162.9, 148.3, 134.2, 133.2, 129.5, 126.7, 125.5, 63.7, 61.9, 54.1, 43.5, 20.8, 14.1, 11.2. IR (KBr): ν 1770, 1731, 1526, 1349, 1190, 1041 cm−1. HRMS (ESI) calcd for C15H19N2O5 [M + H]+: 307.1288; found 307.1294.
Ethyl cis-4-(2-nitrophenyl)-1-propylazetidin-2-one-3-carboxylate (6d): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 8.18 (dd, J = 8.2, 1.1 Hz, 1H), 7.72–7.71 (m, 1H), 7.66–7.62 (m, 1H), 7.55–7.53 (m, 1H), 5.52 (d, J = 5.9 Hz, 1H), 4.62 (d, J = 5.9 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 3.72–3.61 (m, 1H), 3.03–2.97 (m, 1H), 1.70–1.58 (m, 2H), 0.94 (t, J = 7.4 Hz, 4H), 0.90 (t, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 165.4, 163.3, 147.8, 133.6, 131.6, 129.3, 128.7, 125.4, 61.1, 60.4, 54.2, 43.6, 20.6, 13.7, 11.5. IR (KBr): ν 1770, 1731, 1526, 1349, 1190, 1041 cm−1. HRMS (ESI) calcd for C15H19N2O5 [M + H]+: 307.1288; found 307.1288.
Ethyl trans-4-(3-nitrophenyl)-1-propylazetidin-2-one-3-carboxylate (4r): Only the trans-4r was isolated, and the characteristic data are given as following. Yellowish oil. Yield: 54% (82 mg).1H-NMR (400 MHz, CDCl3): 8.29–8.20 (m, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.65 (dd, J = 7.8 Hz, 1H), 5.00 (d, J = 2.2 Hz, 1H), 4.34–4.28 (m, 1H), 4.28–4.22 (m, 1H), 3.87 (d, J = 2.2 Hz, 1H), 3.55–3.43 (m, 1H), 2.95–2.83 (m, 1H), 1.63–1.49 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.2, 161.9, 148.7, 139.1, 132.4, 130.3, 123.9, 121.7, 63.4, 62.0, 56.4, 43.0, 20.8, 14.0, 11.2. IR (KBr): ν 1770, 1735, 1533, 1351, 1200, 1093, 1041, 1013 cm−1. HRMS (ESI) calcd for C15H19N2O5 [M + H]+: 307.1288; found 307.1288.
Ethyl trans-4-(4-nitrophenyl)-1-propylazetidin-2-one-3-carboxylate (4s): Only the trans-4s was isolated, and the characteristic data are given as following. Known compound [47]. Colorless crystals, Yield: 58% (95 mg). M.p.: 84–85 °C. 1H-NMR (400 MHz, CDCl3): 8.28 (d, J = 8.6 Hz, 2H, ArH), 7.54 (d, J = 8.6 Hz, 2H, ArH), 4.98 (d, J = 2.1 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.84 (d, J = 2.1 Hz, 1H), 3.53–3.43 (m, 1H), 2.91–2.84 (m, 1H), 1.62–1.49 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.3, 161.9, 148.3, 144.0, 127.5, 124.4, 63.4, 62.1, 56.4, 43.1, 20.9, 14.0, 11.3.
Ethyl trans-1-methyl-2-(2-nitrophenyl)-4-oxoazetidine-3-carboxylate (4a): Compounds trans-4a and cis-6a were isolated as a mixture, with a trans/cis ratio as 85:15. Yellowish oil. Total yield: 18% (28 mg). 1H-NMR (400 MHz, CDCl3): 8.12 (dd, J = 8.2, 1.1 Hz, 1H), 7.74 (ddd, J = 7.6, 7.6, 0.9 Hz, 1H), 7.60–7.50 (m, 2H), 5.25 (d, J = 2.4 Hz, 1H), 4.40–4.33 (m, 1H), 4.33–4.27 (m, 1H), 3.83 (d, J = 2.4, 1H), 2.97 (d, J = 0.6 Hz, 3H), 1.34 (t, J = 7.1 Hz, 4H). 13C-NMR (100 MHz, CDCl3): 166.5, 162.9, 145.4, 134.3, 133.0, 129.5, 126.5, 125.6, 64.3, 62.0, 56.3, 28.4, 14.1. IR (KBr): ν 1772, 1731, 1526, 1349, 1260, 1190, 1085 cm−1. HRMS (ESI) calcd for C13H15N2O5 [M + H]+: 279.0975; found 279.0977.
Ethyl cis-1-methyl-2-(2-nitrophenyl)-4-oxoazetidine-3-carboxylate (6a): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 8.20 (dd, J = 8.2, 1.2 Hz, 1H), 7.60–7.50 (m, 1H), 7.35–7.27 (m, 2H), 5.43 (d, J = 5.8 Hz, 1H), 4.65 (d, J = 5.8 Hz, 1H), 3.84 (q, J = 7.2 Hz, 2H), 2.98 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). IR (KBr): ν 1772, 1731, 1526, 1349, 1260, 1190, 1085 cm−1. HRMS (ESI) calcd for C13H15N2O5 [M + H]+: 279.0975; found 279.0977.
Ethyl trans-1-benzyl-2-(2-nitrophenyl)-4-oxoazetidine-3-carboxylate (4e): Compounds trans-4e and cis-6e were isolated as a mixture, with a trans/cis ratio as 95:5. Yellowish oil. Yield 34% (60 mg). 1H-NMR (400 MHz, CDCl3): 8.07 (dd, J = 8.2, 1.1 Hz, 1H), 7.70 (td, J = 7.8, 0.9 Hz, 1H), 7.55 (ddd, J = 15.5, 8.2, 4.1 Hz, 2H), 7.35–7.27 (m, 3H), 7.26–7.21 (m, 2H), 5.16 (d, J = 2.4 Hz, 1H), 5.02 (d, J = 15.3 Hz, 1H), 4.38–4.31 (m, 1H), 4.31–4.24 (m, 1H), 4.05 (d, J = 15.3 Hz, 1H), 3.85 (d, J = 2.1 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.3, 163.0, 148.1, 134.1, 134.0, 133.0, 129.4, 128.9, 128.2, 128.1, 126.7, 125.5, 64.0, 61.9, 54.1, 45.8, 20.9, 14.0. IR (KBr): ν 1771, 1735, 1526, 1348, 1188 cm−1. HRMS (ESI) calcd for C19H19N2O5 [M + H]+: 355.1288; found 355.1294.
Ethyl trans-1-(tert-butyl)-2-(2-nitrophenyl)-4-oxoazetidine-3-carboxylate (4f): Yellowish oil. Yield 33% (51 mg). 1H-NMR (400 MHz, CDCl3): 8.01 (dd, J = 8.2, 1.0 Hz, 1H), 7.83 (dd, J = 7.9, 1.1 Hz, 1H), 7.75–7.69 (m, 1H), 7.55–7.49 (m, 1H), 5.34 (d, J = 2.3 Hz, 1H), 4.38–4.31 (m, 1H), 4.31–4.24 (m, 1H), 3.61 (d, J = 2.3 Hz, 1H), 1.34 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.6, 163.2, 148.2, 135.2, 133.7, 129.3, 127.3, 125.0, 62.7, 61.9, 55.4, 52.4, 27.8, 14.1. IR (KBr): ν 1766, 1732, 1370, 1348, 1321, 1259, 1224, 1183 cm−1. HRMS (ESI) calcd for C16H21N2O5 [M + H]+: 321.1445; found 321.1452.
Ethyl cis-1-(tert-butyl)-2-(2-nitrophenyl)-4-oxoazetidine-3-carboxylate (6f): Yellowish oil. Yield 18% (22 mg). 1H-NMR (400 MHz, CDCl3): 8.08 (dd, J = 8.2, 1.1 Hz, 1H), 7.86 (dd, J = 7.9, 1.0 Hz, 1H), 7.72–7.66 (m, 1H), 7.56–7.48 (m, 1H), 5.58 (d, J = 6.3 Hz, 1H), 4.48 (d, J = 6.3 Hz, 1H), 3.78 (q, J = 7.2 Hz, 2H), 1.35 (s, 10H), 0.87 (t, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 165.4, 164.2, 148.2, 133.0, 132.9, 129.4, 129.3, 125.0, 61.1, 58.9, 55.4, 52.6, 27.8, 13.6. IR (KBr): ν 1766, 1734, 1371, 1348, 1322, 1259, 1223, 1183 cm−1. HRMS (ESI) calcd for C16H21N2O5 [M + H]+: 321.1445; found 321.1452.
Ethyl trans-1-(tert-butyl)-4-phenylazetidin-2-one-3-carboxylate (4t): Known compound [49]. Colorless crystals, yield 69% (95 mg); M.p.: 91–94 °C. 1H-NMR (400 MHz, CDCl3): 7.41–7.32 (m, 5H, ArH), 4.85 (d, J = 2.0 Hz, 1H), 4.234 (q, J = 7.2, 1H), 4.225 (q, J = 7.2, 1H), 3.69 (d, J = 2.0 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.27 (s, 9H).

4. Conclusions

In conclusion, the ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with C-2-nitroarylimines, as well as in Staudinger cycloadditions of ethoxycarbonylketene with C-2-nitroarylimines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, sulfa-Staudinger and Staudinger cycloadditions deliver the corresponding cis-β-sultams and cis-β-lactams in considerable amounts, respectively, together with the corresponding predominant trans-β-sultams and trans-β-lactams. In other cases without C-2-nitroarylimines, the above sulfa-Staudinger and Staudinger cycloadditions produce trans-β-sultams and trans-β-lactams, respectively, in excellent diastereoselectivities (trans/cis ratios from 97:3 to 100:0). Further mechanistic rationalization discloses that the ortho-nitro effect is attributed to its strong electron-withdrawing inductive effect rather than the steric hindrance of the 2-nitroaryl group and the electrostatic interaction between the ortho-nitro group and the ethoxycarbonyl group. The current research provides further insights into the diastereoselective control in sulfa-Staudinger and Staudinger cycloadditions.

Supplementary Materials

Copies of 1H-NMR and 13C-NMR spectra of unknown products and 1H-NMR spectra of representative crude reaction mixtures are included in the Supporting Information.

Acknowledgments

This work was supported in part by the National Basic Research Program of China (No. 2013CB328905), the National Natural Science Foundation of China (Nos. 21372025 and 21172017), the BUCT Fund for Disciplines Construction and Development (Project No. XK1533), and the China Postdoctoral Science Foundation (No. 2016M600900).

Author Contributions

Jiaxi Xu conceived and designed the experiments; Zhanhui Yang and Hassane Abdellaoui performed the experiments; Wei He performed the additional experiments during revision; Jiaxi Xu and Zhanhui Yang analyzed the data; Jiaxi Xu and Zhanhui Yang wrote and revised the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 3, 4, 5, and 6 are available from the authors.
Molecules 22 00784 sch001 550
Scheme 1. Diastereoselectivities in sulfa-Staudinger and Staudinger cycloadditions.
Scheme 1. Diastereoselectivities in sulfa-Staudinger and Staudinger cycloadditions.
Molecules 22 00784 sch001
Molecules 22 00784 sch002 550
Scheme 2. Mechanism of sulfa-Staudinger cycloadditions.
Scheme 2. Mechanism of sulfa-Staudinger cycloadditions.
Molecules 22 00784 sch002
Molecules 22 00784 sch003 550
Scheme 3. Sulfenolate-iminium vs. enolate-iminium intermediates in the sulfa-Staudinger cycloadditions involving acylsulfenes.
Scheme 3. Sulfenolate-iminium vs. enolate-iminium intermediates in the sulfa-Staudinger cycloadditions involving acylsulfenes.
Molecules 22 00784 sch003
Molecules 22 00784 g001 550
Figure 1. Ortho-nitro effect by possible electrostatic interaction.
Figure 1. Ortho-nitro effect by possible electrostatic interaction.
Molecules 22 00784 g001
Molecules 22 00784 g002 550
Figure 2. Key zwitterionic intermediates involved in sulfa-Staudinger and Staudinger cycloadditions.
Figure 2. Key zwitterionic intermediates involved in sulfa-Staudinger and Staudinger cycloadditions.
Molecules 22 00784 g002
Table
Table 1. Sulfa-Staudinger cycloadditions involving C-nitrophenyl imines a.
Table 1. Sulfa-Staudinger cycloadditions involving C-nitrophenyl imines a.
Molecules 22 00784 i001
EntryR1NO2ImineR2Yield (%) btrans/cis Ratio c7
1EtO2C2-NO22aMe663a:5a82:180
2EtO2C3-NO22bMe79 d3b:5b100:013
3EtO2C4-NO22cMe41 d3c:5c100:03
4EtO2C2-NO22dn-Pr663d:5d86:140
5EtO2C2-NO22eBn713e:5e88:120
6EtO2C2-NO22ft-Bu653f:5f97:30
7Ph2-NO22aMe363ac:5ac52:480
8Ph3-NO22bMe303bc:5bc54:460
9Ph4-NO22cMe373cc:5cc43:570
10 eEtO2C2-NO22aMe973a:5a63:370
11 eEtO2C3-NO22bMe923b:5b100:00
12 eEtO2C4-NO22cMe993c:5c100:00
a Reactions conducted on a 0.5-mmol scale based on sulfonyl chloride; The data in entries 1–3 were directly cited from refs. [27,28]. b Isolated total yield; c Ratios were determined by the 1H-NMR analysis of the isolated mixture. d Also see ref. [27]. e These reactions were performed with 1.2 equivalents of sulfonyl chloride 1a, 1.0 equivalent of imines 2a–c, and 1.2 equivalents of pyridine.
Table
Table 2. Sulfa-Staudinger reactions of C-2-substitutedaryl imines with ethoxycarbonylmethanesulfonyl chloride (1a) a.
Table 2. Sulfa-Staudinger reactions of C-2-substitutedaryl imines with ethoxycarbonylmethanesulfonyl chloride (1a) a.
Molecules 22 00784 i002
EntryImineR3R4Yield (%) btrans/cis Ratio c
12aNO2H663a:5a82:18
22gMeH553:5g99:1
32hCF3H373h:5h97:3
42iOMeH783i:5i99:1
52jFH723j:5j95:5
62kClH683k:5k97:3
72lBrH703l:5l97:3
82mCl6-Cl533m:5m99:1
92nPhH693n:5n100:0
102o Molecules 22 00784 i003853o:5o100:0
112pNO24-NO2603p:5p75:25
122qNO25-MeO873q:5q56:44
a Reactions conducted on a 0.5-mmol scale based on sulfonyl chloride. b Isolated total yield. c Ratios were determined by the 1H-NMR analysis of the isolated mixture.
Table
Table 3. Ortho-nitro effect in Staudinger reactions a.
Table 3. Ortho-nitro effect in Staudinger reactions a.
Molecules 22 00784 i004
EntryImineR1R2Yield (%) bTrans/cis Ratio c
12d2-NO2Pr434d:6d83:17
22r3-NO2Pr544r:6r100:0
32s4-NO2Pr584s:6s100:0
42a2-NO2Me184a:6a85:15
52e2-NO2Bn344e:6e81:19
62f2-NO2t-Bu514f:6f64:36
72tHt-Bu744t:6t100:0
a Reactions conducted a on 0.5-mmol scale based on imine 2; b Isolated total yield; c Ratios were determined by the 1H-NMR analysis of the reaction mixture.

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Yang, Z.; Abdellaoui, H.; He, W.; Xu, J. Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions. Molecules 2017, 22, 784. https://doi.org/10.3390/molecules22050784

AMA Style

Yang Z, Abdellaoui H, He W, Xu J. Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions. Molecules. 2017; 22(5):784. https://doi.org/10.3390/molecules22050784

Chicago/Turabian Style

Yang, Zhanhui, Hassane Abdellaoui, Wei He, and Jiaxi Xu. 2017. "Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions" Molecules 22, no. 5: 784. https://doi.org/10.3390/molecules22050784

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