o-Phenylenediacetic Acid Anhydride in the Castagnoli–Cushman Reaction: Extending the Product Space to ε-Lactams

Abstract

The diversity of lactam products accessible by the Castagnoli–Cushman reaction (CCR) of imines and dicarboxylic acid anhydrides has been extended to privileged ε-lactams. This novel variant of the CCR using o-phenylenediacetic anhydride is often high-yielding and remarkably diastereoselective and allows the use of α-C–H imines.

The Castagnoli–Cushman reaction (CCR) of α-C–H acidic dicarboxylic acid anhydrides 1 with imines 2 (as well as various analogues) represents a fully atom-economical, formal cycloaddition process and an experimentally convenient way to access a range of polysubstituted lactam carboxylic acids 3 (Scheme [1]).[1] Recently, synthetic strategies based on the CCR as a key scaffold-forming event have received increased attention from the drug discovery community owing to its propensity[2] to deliver leadlike small molecules.[3] Mechanistically, the reaction is thought to proceed via two key events, namely, the acylation of the imine nitrogen atom and a Mannich-type formation of a new C–C bond. In which sequence these two events occur is determined by the specific structure of the reaction components.[4] Following the initial discovery of the reaction for succinic (1a) and glutaric (1b) anhydrides by Castagnoli and Cushman,[5] the range of anhydrides was extended to include, notably, homophthalic anhydride (HPA, 1c)[6] and heteroatom-containing versions 1d [7] and 1e,f,[8] thus significantly broadening the scaffold diversity of 3 accessible by the CCR.[9] These modifications of 1 are significant as they increase the α-C–H acidity of the latter and thus facilitate[10] [11] [12] the Mannich step which is key in the formation of 3. The diversity of lactams available via the CCR was limited to δ- and γ-lactams and did not include their ε-lactam congeners, most likely due to the less favorable entropy associated with the formation of a seven-membered ring.[13]

We reasoned that this limitation could be circumvented via the use of o-phenylenediacetic acid anhydride (1g). While the α-C–H acidity of the latter is lower than that of HPA[14] (as the homologation excludes the other carbonyl function from the conjugation with the respective carbanion), the rigid phenyl linker between the two reactive sides in 1g could alleviate the unfavorable entropic factor,[13] facilitate the formation of the ε-lactam ring 4 (Scheme [1]) and provide a fundamentally new and convenient entry into the 2,3,4,5-tetrahydro-1H-benzo[d]azepine scaffold, which is central to a number of biologically active and naturally occurring compounds and can, therefore, be regarded as privileged.[15] This is exemplified by the ion channel blocker ivabradine (5, Corlanor^®) used to treat ischemia,[16] 5-HT_2С agonist 6 for potential weight management,[17] Eli Lilly’s γ-secretase inhibitor semagacestat (7), which was in phase III clinical trials for Alzheimer’ disease but stopped due to unfavorable toxicology profile,[18] anaplastic lymphoma kinase (ALK) inhibitor 8 for cancer treatment,[19] and the cephalofortunone alkaloid (9) isolated from Cephalotaxus fortune Hook (Figure [1]).[20]

At the time of preparing this manuscript, a similar approach to ε-lactams was disclosed by Ryabukhin and co-workers.[21] In this Letter, we present our results in this area. Reaction of 1g (prepared by a modified literature procedure[22]) with a range of imines 2 in refluxing toluene[23] indeed furnished the desired ε-lactams 4a–u in moderate to excellent chemical yields and medium to very high diastereoselectivity, with a clear preference for the trans diastereomer (except for compound 4r, vide infra), which is a common result for the CCR (Table [1]).[24]

For the imines derived from aromatic aldehydes, the outcome of the reaction appears to be insensitive to the nature of substituents on the imine component. Successful involvement of imines derived from nonenolizable aliphatic aldehydes (such cyclopropanecarboxaldehyde) in the CCR of HPA has been documented in the literature.[2] Therefore, the formation of compound 4s in 50% yield and high diastereoselectivity is in line with previous findings. However, what constitutes a particularly noteworthy result is the formation, in moderate yields, of ε-lactams 4k, 4t, and 4u which are derived from enolizable α-C–H aliphatic aldehydes. We have previously shown that anhydrides 1d–f exclusively form enamide adducts with such aldehydes[8] and have even used this high-yielding transformation in a three-component synthesis of enamide modules for isoxazoline synthesis.[26] Although we could not detect the respective enamides 10 in the reaction mixtures from which 4k, 4t, and 4u were isolated, the major byproducts in all three cases were monoamides 11, presumably formed from 10 on reaction workup (Scheme [2]). The fact that the desired ε-lactams 4k, 4t, and 4u did form in these reactions (albeit in low yield) argues for the reactivity of 1g being somewhat intermediate between that of HPA (as some α-C–H imines have been reported to undergo the CCR with the latter[27]) and of saturated dicarboxylic acid anhydrides (considering that the undesired reaction course was quite a significant contributor to the product distribution).

Table 1 Synthesis of 4-Oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic Acids 4a–u Prepared via the CCR Involving 1g [25]

4a 87% (dr 10:1)a	4b 95% (dr >20:1)	4c 59% (dr 5:1)a
4d 96% (dr 13:1)	4e 90% (dr >20:1)	4f 87% (dr >20:1)
4g 71% (dr 3:1)	4h 71%b (dr >20:1)	4i 86% (dr >20:1)
4j 75% (dr >20:1)	4k 29%c (dr 9:1) a	4l 79% (dr >20:1)
4m 90% (dr 19:1)	4n 92% (dr >20:1)	4o 67% (dr >20:1)
4p 81% (dr 9:1)	4q 51%b (dr >20:1)	4r 89% (dr 2.5:1)d
4s 50% (dr >20:1)	4t 14%c (dr >20:1)	4u 14% (dr >20:1)

^a Crystallized from MeCN.

^b Yield after esterification (MeI, K₂CO₃, acetone, r.t., 24 h) and chromatographic purification.

^c Isolated by HPLC.

^d Major diastereomer: cis.

Table 2 ³ J _H(1)–H(2) Values for Stereoisomers of Compounds 4a–u

Compound	3 J HH trans, Hz	3 J HH cis, Hz
4a	9.6	3.0
4b	9.4	NDa
4c	8.2	1.8
4d	7.0	1.2
4e	8.9	NDa
4f	9.7	1.6
4g	11.1	1.7
4h	7.2	1.7
4i	8.4	1.5
4j	10.6	2.0
4k	6.0	4.5
4l	7.2	1.3
4m	8.3	2.4
4n	8.9	2.6
4o	8.8	1.6
4p	7.7	1.6
4q	6.7	1.4
4r	11.9	1.4
4s	11.1	NDa
4t	6.2	NDa
4u	6.2	NDa

^a ND: signals of minor isomer were not detected due to low content or overlapping.

The trans stereochemistry of the majority of the products was confirmed by the significantly higher ³ J _H(1)–H(2) values observed for the trans diastereomers compared to their cis counterparts (Table [2]). While the coupling-constant range may have a limited utility for stereochemistry assignment of the CCR-derived γ- and δ-lactams,[2] in the case of ε-lactams disclosed herein, the distinction proved to be rather pronounced and was correlated with the single-crystal X-ray structures obtained for compounds 4d, 4f, and 4k (Figure [2]).[28] This allowed us to conclude that compound 4r prepared from 3,4-dihydroisoquinoline as a cyclic imine component formed with a reverse (and much lower, compared to all other cases) diastereoselectivity, with a preference for cis diastereomer. This result is particularly intriguing considering the fact that cis-configured lactam scaffolds can seldom be obtained by the CCR in toluene.[29] This constitutes a valuable finding from a chemical diversity perspective as the cis- and trans-configured CCR lactams represent distinct scaffolds from a medicinal chemistry standpoint.[30]

In conclusion, we have reported an application of the Castagnoli–Cushman reaction to the preparation of privileged ε-lactams using o-phenylenediacetic anhydride. The possibility of using α-C–H imines in these reactions has been demonstrated; in contrast to a few isolated examples reported for homophthalic anhydride. These findings are in line with the results reported by Ryabukhin and co-workers at the time we were preparing this manuscript,[21] significantly expand the product space amenable by this important atom-economical reaction and lay the foundation for exploring further opportunities to apply the CCR towards the construction of seven-membered cyclic frameworks.

No conflict of interest has been declared by the author(s).

Acknowledgement

This research was supported by the Russian Scientific Fund (project grant 14-50-00069). We are grateful to the Research Centre for Magnetic Resonance, the Centre for Chemical Analysis and Materials Research and the Centre for X-ray Diffraction Methods of Saint Petersburg State University Research Park for the analytical data.

• References and Notes

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• 23 General Procedure for Castagnoli–Cushman Reaction of o-Phenylenediacetic Anhydride (1g) and Imines 2 A mixture of o-phenylenediacetic anhydride (1g, 1 equiv) and corresponding imine 2 (1 equiv) in dry toluene (2 mL/1 mmol) was stirred at 110 °C in a screw-cap vial for 2–18 h. The progress of the reaction was monitored by NMR spectroscopy. Compounds 4a–u were isolated from the reaction mixture using one of the following methods. Method A (4a,e–g,i–j,m–p,r,t) The crude reaction product was precipitated from the reaction mixture by dilution of the latter with n-hexane and the precipitate washed with hot MeCN (or crystallized from MeCN) to give pure compound 4. Method B (4b–d,k–l,u) CHCl₃ (25 mL/1 mmol) and sat. NaHCO₃ solution (25 mL/1 mmol) were added to the reaction mixture. After vigorous stirring (30 min), the layers were separated. The aqueous layer was further extracted with CHCl₃ (20 mL/1 mmol) and acidified to pH 1 by careful addition of concd HCl at 0 °C. The precipitate was filtered, washed with water, and air-dried to give pure compound 4. Method C (4h,q)The reaction mixture was concentrated in vacuo to give the crude product, which was converted into the corresponding methyl ester by treatment with MeI (1.5 equiv) in acetone (10 mL) in the presence of K₂CO₃ (1.5 equiv) at r.t. for 24 h. Following filtration and concentration of the filtrate in vacuo, the crude methyl ester was purified by column chromatography on silica gel using an appropriate gradient of EtOAc in hexanes as eluent to provide the analytically pure methyl ester derivative of 4.
• 24 Lepikhina A, Bakulina O, Dar’in D, Krasavin M. RSC Adv. 2016; 6: 83808-83808
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• 25 Characterization Data of Representative Compounds Compound 4a: white solid; mp 240–242 °C (MeCN). ¹H NMR (400 MHz, DMSO-d ₆, 80 °C): δ = 12.34 (br s, 1 H, CO₂H), 7.31 (dd, J = 7.4, 1.3 Hz, 1 H), 7.28–7.23 (m, 2 H), 7.19 (td, J = 7.4, 1.5 Hz, 1 H), 7.14–7.07 (m, 3 H), 7.04 (d, J = 7.3 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 6.95 (dd, J = 7.6, 1.5 Hz, 1 H), 6.86–6.78 (m, 3 H), 5.46 (d, J = 9.6 Hz, 1 H, 1-H), 4.73 (d, J = 15.5 Hz, 1 H, α-H), 4.58 (d, J = 9.6 Hz, 1 H, 2-H), 4.15 (d, J = 15.4 Hz, 1 H, 5-H), 4.04 (d, J = 15.4 Hz, 1 H, 5-H), 3.82 (s, 3 H, OCH3), 3.72 (d, J = 15.5 Hz, 1 H, α-H). ¹³C NMR (101 MHz, DMSO-d ₆, 80 °C): δ = 172.3, 170.5, 157.6, 138.2, 135.5, 134.9, 129.8, 129.5, 129.4, 128.9, 128.2, 128.0, 127.6, 127.4, 126.9, 126.6, 120.6, 112.1, 59.7, 56.1, 52.7, 48.9, 43.6. ESI-HRMS: m/z calcd for C₂₅H₂₃NNaO₄ [M + Na]⁺: 424.1519; found: 424.1514. Compound 4h: white solid; mp 114–116 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.20 (m, 2 H), 7.15 (td, J = 7.5, 1.0 Hz, 1 H), 7.07 (d, J = 8.1 Hz, 2 H, 2′,6′-H), 6.89 (d, J = 7.5 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 2 H, 3′,5′-H), 5.30 (d, J = 7.7 Hz, 1 H, 1-H), 4.24 (d, J = 7.7 Hz, 1 H, 2-H), 4.22–4.10 (m, 1 H, CH(CH₃)₂), 3.95 (s, 2 H, 2 × 5-H), 3.80 (s, 3 H), 3.77 (s, 3 H), 1.06 (d, J = 6.7 Hz, 1 H, CHCH₃), 0.99 (d, J = 6.8 Hz, 1 H, CHCH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 172.2, 170.3, 159.0, 135.3, 133.2, 133.2, 129.0, 128.1, 128.0, 127.7, 127.3, 113.9, 60.2, 56.8, 55.2, 52.5, 50.4, 44.7, 20.0, 19.8. ESI-HRMS: m/z calcd for C₂₂H₂₆NO₄ [M + H]⁺: 354.1700; found: 354.1689. Compound 4l: beige solid; mp 190–192 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.12 (br s, 1 H, CO₂H), 7.44 (dd, J = 4.5, 1.7 Hz, 1 H, 3′-H), 7.25–7.12 (m, 4 H), 6.99–6.90 (m, 2 H, 4′-H and 5′-H), 5.47 (d, J = 7.6 Hz, 1 H, 1-H), 4.66 (d, J = 7.7 Hz, 1 H, 2-H), 3.78 (d, J = 15.8 Hz, 1 H, 5-H), 3.65 (d, J = 15.8 Hz, 1 H, 5-H), 2.42–2.31 (m, 1 H, α-H), 0.75–0.67 (m, 2 H, β-CH₂), 0.45–0.38 (m, 2 H, β-CH₂). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 172.9, 172.4, 144.4, 134.5, 134.2, 129.8, 129.6, 128.0, 127.4, 126.1, 125.7, 60.6, 54.8, 44.3, 31.8, 8.9, 8.4. ESI-HRMS: m/z calcd for C₁₈H₁₈NO₃S [M + H]⁺: 328.1002; found: 328.0989.
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• 28 CCDC 1518482 (4d), CCDC 1518076 (4f) and CCDC 1518481 (4k) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• References and Notes

• 1 Gonzalez-Lopez M, Shaw JT. Chem. Rev. 2009; 109: 164-164
  CrossrefSearch in Google Scholar
• 2 Ryabukhin SV, Panov DM, Granat DS, Ostapchuk EN, Kryvoruchko DV, Gkygorenko OO. ACS Comb. Sci. 2014; 16: 146-146
  CrossrefSearch in Google Scholar
• 3 Nadin A, Hattotuwagama C, Churcher I. Angew. Chem. Int. Ed. 2012; 51: 1114-1114
  CrossrefSearch in Google Scholar
• 4 Tang Y, Fettinger JC, Shaw JT. Org. Lett. 2009; 11: 3802-3802
  CrossrefPubMedSearch in Google Scholar
• 5a Castagnoli N. J. Org. Chem. 1969; 34: 3187-3187
  CrossrefSearch in Google Scholar
• 5b Cushman M, Castagnoli N. J. Org. Chem. 1973; 38: 440-440
  CrossrefSearch in Google Scholar
• 6 Cushman M, Gentry J, Dekow FW. J. Org. Chem. 1977; 42: 1111-1111
  CrossrefSearch in Google Scholar
• 7 Burdzhiev N, Stanoeva E, Shivachev B, Nikolova R. C. R. Chim. 2014; 17: 420-420
  CrossrefSearch in Google Scholar
• 8 Dar’in D, Bakulina O, Chizhova M, Krasavin M. Org. Lett. 2015; 17: 3930-3930
  CrossrefSearch in Google Scholar
• 9 Krasavin M, Dar'in D. Tetrahedron Lett. 2016; 57: 1635-1635
  CrossrefSearch in Google Scholar
• 10 Chizhova M, Bakulina O, Dar'in D, Krasavin M. ChemistrySelect 2016; 1: 5487-5487
  CrossrefSearch in Google Scholar
• 11 Cushman M, Madaj EJ. J. Org. Chem. 1987; 52: 907-907
  CrossrefSearch in Google Scholar
• 12 Ng PY, Masse CE, Shaw JT. Org. Lett. 2006; 8: 3999-3999
  CrossrefPubMedSearch in Google Scholar
• 13 Galli C, Mandolini L. Eur. J. Org. Chem. 2000; 3117-3117
• 14 Liu J, Wang Z, Levin A, Emge TJ, Rablen PR, Floyd DM, Knapp S. J. Org. Chem. 2014; 79: 7593-7593
  CrossrefSearch in Google Scholar
• 15 Welsch ME, Snyder SE, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 1-1
  CrossrefPubMedSearch in Google Scholar
• 16 Ruzyllo W, Tendera M, Ford I, Fox KM. Drugs 2007; 67: 393-393
  CrossrefPubMedSearch in Google Scholar
• 17 Prajapati N, Giridhar R, Sinha A, Kanhed AM, Yadav MR. Mol. Diversity 2015; 19: 653-653
  CrossrefSearch in Google Scholar
• 18 Bulic B, Ness J, Hahn S, Rennhack A, Jumpertz T, Weggen S. Curr. Neuropharmacol. 2011; 9: 598-598
  CrossrefSearch in Google Scholar
• 19 Kang GA, Lee M, Song D, Lee HK, Ahn S, Park CH, Lee CO, Yun CS, Jung H, Kim P, Ha JD, Co SY, Kim HR, Hwang JY. Bioorg. Med. Chem. Lett. 2015; 25: 3992-3992
  CrossrefSearch in Google Scholar
• 20 Li H, Wen Y, Wang F, Wu P, Wei X. Tetrahedron Lett. 2015; 56: 5735-5735
  CrossrefSearch in Google Scholar
• 21 Adamovskyi MI, Ryabukhin SV, Sibgatulin DA, Rusanov E, Grygorenko OO. Org. Lett. 2017; 19: 130-130
  CrossrefPubMedSearch in Google Scholar
• 22 Wirta U, Fröhlich R, Wünsch B. Tetrahedron: Asymmetry 2005; 16: 2199-2199
  CrossrefSearch in Google Scholar
• 23 General Procedure for Castagnoli–Cushman Reaction of o-Phenylenediacetic Anhydride (1g) and Imines 2 A mixture of o-phenylenediacetic anhydride (1g, 1 equiv) and corresponding imine 2 (1 equiv) in dry toluene (2 mL/1 mmol) was stirred at 110 °C in a screw-cap vial for 2–18 h. The progress of the reaction was monitored by NMR spectroscopy. Compounds 4a–u were isolated from the reaction mixture using one of the following methods. Method A (4a,e–g,i–j,m–p,r,t) The crude reaction product was precipitated from the reaction mixture by dilution of the latter with n-hexane and the precipitate washed with hot MeCN (or crystallized from MeCN) to give pure compound 4. Method B (4b–d,k–l,u) CHCl₃ (25 mL/1 mmol) and sat. NaHCO₃ solution (25 mL/1 mmol) were added to the reaction mixture. After vigorous stirring (30 min), the layers were separated. The aqueous layer was further extracted with CHCl₃ (20 mL/1 mmol) and acidified to pH 1 by careful addition of concd HCl at 0 °C. The precipitate was filtered, washed with water, and air-dried to give pure compound 4. Method C (4h,q)The reaction mixture was concentrated in vacuo to give the crude product, which was converted into the corresponding methyl ester by treatment with MeI (1.5 equiv) in acetone (10 mL) in the presence of K₂CO₃ (1.5 equiv) at r.t. for 24 h. Following filtration and concentration of the filtrate in vacuo, the crude methyl ester was purified by column chromatography on silica gel using an appropriate gradient of EtOAc in hexanes as eluent to provide the analytically pure methyl ester derivative of 4.
• 24 Lepikhina A, Bakulina O, Dar’in D, Krasavin M. RSC Adv. 2016; 6: 83808-83808
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• 25 Characterization Data of Representative Compounds Compound 4a: white solid; mp 240–242 °C (MeCN). ¹H NMR (400 MHz, DMSO-d ₆, 80 °C): δ = 12.34 (br s, 1 H, CO₂H), 7.31 (dd, J = 7.4, 1.3 Hz, 1 H), 7.28–7.23 (m, 2 H), 7.19 (td, J = 7.4, 1.5 Hz, 1 H), 7.14–7.07 (m, 3 H), 7.04 (d, J = 7.3 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 6.95 (dd, J = 7.6, 1.5 Hz, 1 H), 6.86–6.78 (m, 3 H), 5.46 (d, J = 9.6 Hz, 1 H, 1-H), 4.73 (d, J = 15.5 Hz, 1 H, α-H), 4.58 (d, J = 9.6 Hz, 1 H, 2-H), 4.15 (d, J = 15.4 Hz, 1 H, 5-H), 4.04 (d, J = 15.4 Hz, 1 H, 5-H), 3.82 (s, 3 H, OCH3), 3.72 (d, J = 15.5 Hz, 1 H, α-H). ¹³C NMR (101 MHz, DMSO-d ₆, 80 °C): δ = 172.3, 170.5, 157.6, 138.2, 135.5, 134.9, 129.8, 129.5, 129.4, 128.9, 128.2, 128.0, 127.6, 127.4, 126.9, 126.6, 120.6, 112.1, 59.7, 56.1, 52.7, 48.9, 43.6. ESI-HRMS: m/z calcd for C₂₅H₂₃NNaO₄ [M + Na]⁺: 424.1519; found: 424.1514. Compound 4h: white solid; mp 114–116 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.20 (m, 2 H), 7.15 (td, J = 7.5, 1.0 Hz, 1 H), 7.07 (d, J = 8.1 Hz, 2 H, 2′,6′-H), 6.89 (d, J = 7.5 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 2 H, 3′,5′-H), 5.30 (d, J = 7.7 Hz, 1 H, 1-H), 4.24 (d, J = 7.7 Hz, 1 H, 2-H), 4.22–4.10 (m, 1 H, CH(CH₃)₂), 3.95 (s, 2 H, 2 × 5-H), 3.80 (s, 3 H), 3.77 (s, 3 H), 1.06 (d, J = 6.7 Hz, 1 H, CHCH₃), 0.99 (d, J = 6.8 Hz, 1 H, CHCH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 172.2, 170.3, 159.0, 135.3, 133.2, 133.2, 129.0, 128.1, 128.0, 127.7, 127.3, 113.9, 60.2, 56.8, 55.2, 52.5, 50.4, 44.7, 20.0, 19.8. ESI-HRMS: m/z calcd for C₂₂H₂₆NO₄ [M + H]⁺: 354.1700; found: 354.1689. Compound 4l: beige solid; mp 190–192 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.12 (br s, 1 H, CO₂H), 7.44 (dd, J = 4.5, 1.7 Hz, 1 H, 3′-H), 7.25–7.12 (m, 4 H), 6.99–6.90 (m, 2 H, 4′-H and 5′-H), 5.47 (d, J = 7.6 Hz, 1 H, 1-H), 4.66 (d, J = 7.7 Hz, 1 H, 2-H), 3.78 (d, J = 15.8 Hz, 1 H, 5-H), 3.65 (d, J = 15.8 Hz, 1 H, 5-H), 2.42–2.31 (m, 1 H, α-H), 0.75–0.67 (m, 2 H, β-CH₂), 0.45–0.38 (m, 2 H, β-CH₂). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 172.9, 172.4, 144.4, 134.5, 134.2, 129.8, 129.6, 128.0, 127.4, 126.1, 125.7, 60.6, 54.8, 44.3, 31.8, 8.9, 8.4. ESI-HRMS: m/z calcd for C₁₈H₁₈NO₃S [M + H]⁺: 328.1002; found: 328.0989.
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• 28 CCDC 1518482 (4d), CCDC 1518076 (4f) and CCDC 1518481 (4k) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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