Rhodium-Catalyzed [4 + 3] Annulations of Sulfoximines with α,β

Letter Cite This: Org. Lett. 2017, 19, 6020-6023

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Rhodium-Catalyzed [4 + 3] Annulations of Sulfoximines with α,βUnsaturated Ketones Leading to 1,2-Benzothiazepine 1‑Oxides Jian Wen,‡ Hanchao Cheng,‡ Gerhard Raabe, and Carsten Bolm* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany S Supporting Information *

ABSTRACT: A Cp*Rh(III) complex has been used as catalyst for the preparation of unprecedented 1,2-benzothiazepine 1-oxides by [4 + 3] cyclization of NH-sulfoximines with α,β-unsaturated ketones. For a wide range of substrates with various functional groups, moderate to good product yields were obtained.

[3 + 2] cyclization reactions to yield five-membered heterocycles such as indazoles or indoles.11 A rhodium-catalyzed [4 + 3] annulation of benzamides with α,β-unsaturated aldehydes and ketones was disclosed by Glorius and co-workers.12 Although the reaction proved challenging and was limited in substrate scope, it was important for the development of our synthetic scheme providing access to 1,2-benzothiazepine 1oxides 2. Herein, we report the success of this approach. To initiate the study, S-methyl-S-phenylsulfoximine (3a) and phenyl vinyl ketone (4a) were selected as representative starting materials. The first reaction was performed with a 3fold access of the enone and a combination of [Cp*RhCl2]2 (2.5 mol %) and AgSbF6, (10 mol %) in the presence of pivalic acid (3.0 equiv) in DCE at 100 °C for 14 h. To our delight, annulated heterocycle 2aa was formed, albeit only in 15% yield (Table 1, entry 1). The major product was compound 5aa, presenting the same heterocylic core as 2aa but containing an additional enone-derived tether.13 Considering both compounds 2aa and 5aa synthetically attractive, the subsequent reaction optimization focused on preparing them selectively. First, 2aa was targeted. A screening of solvents revealed that toluene was superior to DCE and THF (Table 1, entries 1−3). Varying the ratio of sulfoximine 3a and enone 4a from 1:1 to 3:1 increased the yield of 2aa to 56% (Table 1, entries 4−6).14 Replacing pivalic acid by 1-adamantanecarboxylic acid or acetic acid afforded product 2aa in 73% and 41% yield, respectively (Table 1, entries 7 and 8).15 Increasing the catalytic loading of [Cp*RhCl2]2 from the commonly used 2.5 mol % to 4.0 mol % had only a minor effect on the yield of 2aa (Table 1, entry 9). Using [RuCl2(p-cymene)]2 as catalyst led to 2aa exclusively, but the yield was low (Table 1, entry 10). Thus, the best conditions for obtaining 2aa were the following: Use of a 3:1 ratio of 3a:4a, 2.5 mol % of [Cp*RhCl2]2, 10 mol % of AgSbF6,

T

ransition-metal-catalyzed C−H bond functionalizations enable chemists to efficiently access compounds with new C−C and C−heteroatom bonds.1 In this context, the construction of heterocycles is particularly important.2 Sulfoximines are molecules with relevance for medicinal chemistry and crop protection.3 Recently, various C−H bond functionalizations of S-aryl sulfoximines have been discovered, including some leading to heterocycles.4,5 For example, in a very straightforward manner, rhodium catalysis allowed access of diversely substituted 1,2-benzothiazine 1-oxides 1 by [4 + 2] annulations of sulfoximines with alkynes,4a diazo compounds,4b and allyl methyl carbonate (Scheme 1).4c,6 We hypothesized Scheme 1. Rhodium-Catalyzed C−H Functionalizations of Sulfoximines Leading to Heterocycles

that this reaction scenario could be extended by using α,βunsaturated carbonyl compounds (enones), which by C−H bond activation/annulation sequences would lead to 7membered heterocycles 2 (1,3-diorganyl-5H-1λ4-benzo[f ][1,2]thiazepine 1-oxides). To our surprise, we noted that the molecular skeleton of 2 was unprecedented.7 Considering that benzothiazepines are generally regarded as privileged scaffolds found in numerous drugs and drug candidates,8,9 this finding was remarkable. In previous reports on applications of α,β-unsaturated aldehydes or ketones in rhodium-catalyzed C−H bond functionalizations it was demonstrated that substrates underwent either Michael additions to afford alkylation products10 or © 2017 American Chemical Society

Received: October 5, 2017 Published: October 18, 2017 6020

DOI: 10.1021/acs.orglett.7b03106 Org. Lett. 2017, 19, 6020−6023

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

entry

3a/4a

additive

solvent

2aa/5aab (%)

1 2 3 4 5 6 7 8 9c 10d 11e 12e,f

1:3 1:3 1:3 1:1 2:1 3:1 3:1 3:1 3:1 3:1 1:3 1:3

PivOH PivOH PivOH PivOH PivOH PivOH 1-AdCO2H AcOH 1-AdCO2H 1-AdCO2H Cu(OAc)2·H2O Cu(OAc)2·H2O

DCE THF toluene toluene toluene toluene toluene toluene toluene toluene DCE DCE

15/50 5/32 28/62 35/48 45/40 56/25 73/5 41/35 72/5 48/0 0/75 0/89

Scheme 2. Substrate Scope Targeting 1,2-Benzothiazepine 1Oxides 2a

a

All reactions were conducted on a 0.3 mmol scale (of 3a or 4a). After column chromatography. cUse of 4 mol % of [Cp*RhCl2]2. d Use of 5 mol % of [RuCl2(p-cymene)]2. eUse of 2 equiv of Cu(OAc)2·H2O. fPerformed in DCE at 70 °C for 6 h. b

3 equiv of 1-adamantanecarboxylic acid in toluene at 100 °C for 14 h (Table 1, entry 7). Under these conditions, 2aa was obtained in 73% yield with 5% of 5aa as byproduct, which could be separated by column chromatography. Adjusting the reaction conditions for a selective preparation of 5aa proved surprisingly straightforward. Thus, replacing PivOH by copper(II) acetate monohydrate led to 5aa in 75% yield as the sole product (Table 1, entry 11). Thus, here, the optimal conditions (on a 0.3 mmol scale) were as follows: use of a 1:3 ratio of 3a:4a, 2.5 mol % of [Cp*RhCl2]2, 10 mol % of AgSbF6, 2 equiv of Cu(OAc)2·H2O in DCE at 70 °C for 6 h. Accordingly, 5aa was obtained in 89% yield after column (Table 1, entry 12).16 With the optimal conditions in hand, the substrate scope was investigated. First, we targeted 1,2-benzothiazepine 1-oxides 2. Scheme 2 shows the results obtained by varying the sulfoximine structure and keeping 4a as reaction partner. Generally, all substrate combinations reacted well, affording the desired products 2 in yields ranging from 45% to 75%. Annulations of S-aryl-S-methylsulfoximines leading to 2aa−ka showed that various substituents on the arene (halo, nitro, carboxyl, and acyl groups) were tolerated. Electronic effects played only a minor role. The regioselective formation of 2ia revealed that the C−H bond functionalization preferentially occurred at the less sterically hindered side of the sulfoximidoyl substituent. It is noteworthy that substrates with ortho-substituents on the arene reacted in the same manner as indicated by the formation of benzothiazepine 1-oxides 2ja and 2ka, which were obtained in 75% and 68% yield, respectively. In addition, reactions with Sphenylsulfoximines bearing S-ethyl, S-cyclopropyl, and S-benzyl substituents proceeded smoothly, providing 2la−na in yields of between 69% and 71%. Compared to the conversion of Smethyl-S-phenylsulfoximine leading to 2aa, S,S-diphenylsulfoximine gave the corresponding product 2oa in a slightly lower yield (73% versus 55%). Next, the enone component 4 was varied employing NHsulfoximine 3a as the coupling partner (Scheme 2). In general, aryl vinyl ketones reacted well irrespective of the substitution

a

Reaction conditions: sulfoximine 3 (0.90 mmol), ketone 4 (0.30 mmol), [Cp*RhCl2]2 (7.5 × 10−3 mmol), AgSbF6 (0.03 mmol), 1AdCO2H (2.70 mmol), toluene (3 mL), 100 °C, 14 h. bReaction scale: 1 mmol with respect to ketone 4a.

pattern on the arene. Neither electronic factors nor the position of the substituent significantly affected the yields of the resulting products, which ranged from 53% to 77% for compounds 2ab−an. Products 2ad, 2ae, 2ak, and 2al are interesting because the halo substituents might be useful for subsequent cross-coupling reactions. 2-Thiophene-yl and 2furanyl vinyl ketones led to benzothiazepine 1-oxides 2am and 2an in 53% and 61% yield, respectively. Indene-fused product 2ao was obtained from the corresponding 2-methylene-dihydro indenone derivative in 41% yield. Unfortunately, no product was found when ethyl vinyl ketone was applied (not shown), and cyclohexyl vinyl ketone gave only a trace of 2ap, both indicating that alkyl vinyl ketones were unsuitable substrates. 6021

DOI: 10.1021/acs.orglett.7b03106 Org. Lett. 2017, 19, 6020−6023

Letter

Organic Letters The selective synthesis of substituted benzothiazepine 1oxides 5 was targeted next. Under the aforementioned optimized reaction conditions, various sulfoximine/enone combinations were examined (Scheme 3). In reactions with

Scheme 4. Plausible Mechanism

Scheme 3. Substrate Scope Targeting 1,2-Benzothiazepine 1Oxides 5a

Scheme 5. Oxidative Cleavage Reactions of the Productsa

a

Conditions: sulfoximine 1 (0.30 mmol), ketone 2 (0.90 mmol), [Cp*RhCl2]2 (7.5 × 10−3 mmol), AgSbF6 (0.03 mmol), Cu(OAc)2· H2O (0.60 mmol), DCE (3 mL), 70 °C, 6 h. bReaction scale: 1 mmol with respect to sulfoximine 3a.

4a, neither the substitution pattern of the S-aryl nor the nature of the S-alkyl substituent of the sulfoximine showed a significant effect on the yield of the corresponding products (5aa−na). When sulfoximine 3a was coupled with 4-chlorophenyl- and furanyl-substituted vinyl ketones products 5ad and 5an were obtained in yields of 92% and 78%, respectively. The reaction of sulfoximine 3q having an m-bromo group on the arene and 4a produced a 1:1 mixture of regioisomers 5qa and 5qa′ in an overall yield of 84%. A plausible mechanism for the coupling is shown in Scheme 4. First, sulfoximine 3 reacts with Rh(III) species A to form five-membered rhodacycle B by C−H bond activation.5 Coordination of enone 4 to B provides complex C, which upon olefin insertion leads to cyclic intermediate D. Product 2 is then formed by double protonation of D and subsequent dehydration of ortho-functionalized sulfoximine E. In the presence of an excess of enone 4, E undergoes a second ortho-functionalization to provide product 5 after subsequent monodehydration.16 With the goal of developing a feeling for the chemical reactivity of the products, solutions of benzothiazepines 2aa and 5aa in DCM were treated with m-CPBA (2.0 equiv) in the presence of aq NaHCO3 (Scheme 5). As a result, the double bond of the heterocycle was cleaved, and N-benzoyl sulfoximines 6a and 6b were obtained in yields of 76% and 74%, respectively.17 In conclusion, we have developed a novel rhodium-catalyzed [4 + 3] annulation of NH-sulfoximines with α,β-unsaturated ketones providing unprecedented benzothiazepine 1-oxides in

a

Conditions: benzothiazepine 1-oxides 2aa or 5aa (0.2 mmol), mCPBA (0.4 mmol), aq. NaHCO3 (0.5 M), DCM (10 mL), rt, 24 h.

moderate to good yields.18 A mechanistic scheme has been proposed, and the oxidative cleavage of the double bond in the heterocycle was demonstrated.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03106. X-ray data for compound 5aa (CIF) General information and experimental procedures, product characterization data, X-ray crystal structure of 5aa, 1H NMR, 13C NMR, and 19F NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Homepage: http:// bolm.oc.rwth-aachen.de/. Fax: (+49) 241-8092-391. ORCID

Carsten Bolm: 0000-0001-9415-9917 6022

DOI: 10.1021/acs.orglett.7b03106 Org. Lett. 2017, 19, 6020−6023

Letter

Organic Letters Author Contributions

Kang, E.; Zhang, Y.; McPhail, A. T.; Carroll, S. S.; Burlein, C.; Munshi, V.; Orth, P.; Strickland, C. J. Med. Chem. 2011, 54, 7176. (10) (a) Li, J.; Zhang, Z.; Ma, W.; Tang, M.; Wang, D.; Zou, L.-H. Adv. Synth. Catal. 2017, 359, 1717. (b) Liu, B.; Hu, P.; Zhou, X.; Bai, D.; Chang, J.; Li, X. Org. Lett. 2017, 19, 2086. (c) Li, S.-S.; Li, W.-H.; Zhang, G.-T.; Xia, Y.-Q.; Liu, C.-F.; Su, F.; Zhang, X.-M.; Dong, L. Org. Biomol. Chem. 2016, 14, 7859. (d) Boerth, J. A.; Ellman, J. A. Chem. Sci. 2016, 7, 1474. (e) Boerth, J. A.; Hummel, J. R.; Ellman, J. A. Angew. Chem., Int. Ed. 2016, 55, 12650. (f) Zhang, Z.; Tang, M.; Han, S.; Ackermann, L.; Li, J. J. Org. Chem. 2017, 82, 664. (g) Lan, Y.; Yang, C.; Xu, Y.-H.; Loh, T.-P. Org. Chem. Front. 2017, 4, 1411. (11) Cai, S.; Lin, S.; Yi, X.; Xi, C. J. Org. Chem. 2017, 82, 512. (12) Shi, Z.; Grohmann, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5393. (13) The crystal structure of 5aa was determined by X-ray diffraction analysis. CCDC-1564782 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre. (14) Changing the ratio of 2a:3a to 5:1 (in toluene at 100 °C) increased the yield of 2aa further (see the Supporting Information for details), but for practical reasons, the subsequent reactions were performed with a 3:1 ratio of both starting materials. (15) Extending the reaction time from 14 to 20 h led to 61% yield of 2aa (for details, see the Supporting Information). (16) Subjecting 2aa to the standard reaction conditions did not lead to 5aa indicating that the former compound is not an intermediate on the reaction path toward the latter product. (17) Although mechanistic details of this C−C bond cleavage are unknown, we assume that it proceeds via the corresponding epoxides, which are hydrolyzed under these conditions. For an analogous transformation in the chemistry of 1,2-benzothiazine 1-oxides, see ref 4a. (18) Here, only racemic sulfoximines were used. For well-established synthetic routes towards enantiopure substrates, which could equally be applied here, see: Dong, S.; Frings, M.; Cheng, H.; Wen, J.; Zhang, D.; Raabe, G.; Bolm, C. J. Am. Chem. Soc. 2016, 138, 2166 and references cited therein.

‡

J.W. and H.C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

J.W. and H.C. thank the China Scholarship Council (CSC) for predoctoral stipends. Dr. José G. Hernández and Dr. Deo Prakash Tiwari (both RWTH Aachen University) are acknowledged for helpful discussions.

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DOI: 10.1021/acs.orglett.7b03106 Org. Lett. 2017, 19, 6020−6023