Letter Cite This: Org. Lett. 2017, 19, 6204-6207
pubs.acs.org/OrgLett
Intermolecular Regio- and Stereoselective Sulfenoamination of Alkenes with Thioimidazoles Nur-E Alom, Yesmin Akter Rina, and Wei Li* Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States S Supporting Information *
ABSTRACT: An intermolecular sulfenoamination reaction utilizing a stable sulfur precursor with a broad range of alkene structures is described. More importantly, these reactions proceed in a highly regio- and stereoselective manner to afford interesting heterocyclic motifs ready for biological studies. In addition, a highly regiodivergent approach to access the opposite regioisomers for styrene derivatives was also developed.
E
Scheme 1. Alkene Sulfenoamination Reactions
lectrophilic activation is an important and fundamental strategy in alkene functionalization reactions.1 Typically, an electrophilic activating group is employed to convert the alkene into an “-iranium” intermediate, followed by nucleophilic addition to give the desired product. The utility of such a strategy relies on the abundant, versatile, and diverse nature of the alkene substrate. Given the frequent appearances of nitrogen and sulfur atoms in pharmaceuticals, agrochemicals, and natural products, the development of vicinal sulfenoamination of alkenes in a regioselective manner is of significant interest to the synthetic and medicinal communities.2 In this context, intramolecular electrophilic sulfur activation for alkene sulfenoamination has been precedented.3 Alternatively, intermolecular protocols with a broad range of alkene and thioamine structures, although rare, represent an attractive complement and modular approach for the elaboration of N- and Scontaining molecules.4 In addition, the adoption of a stable sulfur precursor, in lieu of pregenerated electrophilic sulfur reagents, can further enhance the practicality of the alkene sulfenoamination strategy.5 As part of our interest in heterocycles synthesis directly from alkenes, we are interested in developing intermolecular alkene sulfenoamination methods, to provide N- and S-containing heterocycles. Efforts from the Denmark group and several others have demonstrated regioselective thioamination processes in intramolecular settings.6 The origin and extent of regioselectivity, in these cases, are dependent on the competing endo versus exo trapping of the thiiranium intermediate by a pendant nucleophile (Scheme 1a). Recently, we have demonstrated an intermolecular and regioselective sulfenoamination of terminal olefins, utilizing thioamide as a stable sulfur and nitrogen precursor, in a one-pot process to synthesize thiazolines (Scheme 1b).7 The regioselectivity stems from the initial nucleophilic displacement of a 1,2-dibromoalkane, generated from the halogenation of alkenes, with which the more nucleophilic sulfur atom preferably attacks the more electrophilic carbon of the 1,2-dibromoalkane. © 2017 American Chemical Society
In contrast to this previous halogenation approach, we hypothesize an in situ generation of electrophilic sulfur reagent for alkene activation. After attacking the resulting thiiranium ion by a pendant nitrogen nucleophile at the more electrophilic carbon position, the desired N- and S-containing heterocycle with good regioselectivity can then be obtained.8 We reason that this approach could use a stable sulfur precursor. With this strategy in mind, we report herein an exceptional regio- and stereoselective alkene sulfenoamination reaction with thioimidazole (Scheme 1c). In addition, we have also realized highly regiodivergent thioamination processes of styrene derivatives, while providing evidence for a temperature-dependent thiiranium ion and open carbocation equilibrium. Received: October 7, 2017 Published: October 27, 2017 6204
DOI: 10.1021/acs.orglett.7b03128 Org. Lett. 2017, 19, 6204−6207
Letter
Organic Letters Scheme 2. Scope of the Alkene Substratea
Our study began with the evaluation of a range of sulfur- and nitrogen-containing structures with a halogen source, as sulfur− halogen bonds are common sources of electrophilic sulfur.9 Gratifyingly, our screenings revealed that Selectfluor could enable thiobenzimidazole to readily couple with styrene. The resulting heterocyclic structure 3 could be obtained in high regioselectivity, albeit in low yield (7%), using acetonitrile as a solvent (Table 1, entry 1). 10 Notably in terms of Table 1. Selected Reaction Optimizationsa
entry
solvent (M)
1 (equiv)
Selectfluor (equiv)
yield (%)
1 2 3 4 5 6 7 8b 9c 10d 11 12e
ACN (0.5) DCM (0.5) DMF (0.5) DMF (0.5) DMF (0.5) DMF (0.25) DMF (1.0) DMF (0.5) DMF (0.5) DMF (0.5) DMF (0.5) DMF (0.5)
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.2 1.5
1.0 1.0 1.0 1.2 1.5 1.2 1.2 1.2 1.2 1.2 1.2 1.2
7 0 53 77 56 67 32 55 76 70 78 87 (87)
a
Reaction conditions: styrene 1 (1.0 equiv, 0.5 mmol), 2 (1.0 equiv), Selectfluor (1.0 equiv) at rt for 16 h. Yields are calculated based on crude NMR using 1,3-benzodioxole as the internal standard. b8 h. c24 h. d2 (1.2 equiv). e1 (1.5 equiv, 0.75 mmol), 2 (1.0 equiv, 0.5 mmol), Selectfluor (1.2 equiv) at rt for 16 h. Yield in parentheses is isolated yield.
regioselectivity, heterocycle 3 was produced exclusively as a single regioisomeric product. Excited by our hypothesis validation, we pursued further optimizations to demonstrate that N,N-dimethylformamide (DMF) was a superior solvent, affording 3 in 53% yield (Table 1, entries 2−3). 11 Concentration and Selectfluor stoichiometry assessments led to an increase in yield to 77% (Table 1, entries 4−7). Additional time studies confirmed that 16 h were needed for the reaction to proceed to completion (Table 1, entries 8−9). Finally, simply switching the limiting reagent to thiobenzimidazole resulted in the best reaction conditions, affording the desired heterocycle in 87% isolated yield (Table 1, entries 10− 12). With the optimized conditions in hand, we proceeded to examine the scope of the alkene substrate. A range of styrene derivatives, including a variety of substitutions at the ortho- or para- positions with halogens, alkyls, ethers, and esters, were well tolerated in this reaction (Scheme 2, products 4−12). These alkene substrates underwent the reaction with similar high efficiency and regioselectivity compared to the standard substrate. Moreover, the only regioisomers observed in these reactions are as shown in Scheme 2, with the sulfur atom attached to the terminal position and the nitrogen atom to the benzylic position. To our delight, both trans-β-methylstyrene and indene produced the desired products 13 and 14, respectively, with exceptional yields and diastereoselectivities (Scheme 2, products 13 and 14). In addition, a number of 1,1disubstituted styrene derivatives afforded the desired products,
a
Standard reaction conditions and isolated yields are reported. The regio- and diastereomeric ratios are based on crude NMR. bReaction conducted at 50 °C.
establishing highly steric-congested carbon centers (Scheme 2, products 15−18). The regioselectivities, in these cases, were also consistent with the standard substrate. Furthermore, a 1,2disubstituted aliphatic alkene, trans-4-octene participated in the reaction in good yield with excellent diastereoselectivity (Scheme 2, product 19). Interestingly, exotic tetracyclic structures 20 and 21 could also be generated with the corresponding olefins, further highlighting the synthetic utility of this sulfenoamination strategy (Scheme 2, products 20 and 21). In general, the regioselectivity of aliphatic alkenes could be controlled by steric factors, as the more steric hindered olefin for 22, completely reversing the normally observed regioselectivity (Scheme 2, products 22−25).12 Encouraged by the comprehensive alkene scope, we decided to turn our attention to the incorporation of thioimidazole structures in this reaction. A number of useful functional groups such as alkyl, halogen, ether, difluoromethyl ether, and nitro could be introduced without any detrimental effects in the reaction efficiencies (Scheme 3, products 26−31). In each of these cases, an additional product was observed, with both nitrogen atoms in the benzimidazole ring capable of nucleophilic additions. Regioselectivity with respect to N- and 6205
DOI: 10.1021/acs.orglett.7b03128 Org. Lett. 2017, 19, 6204−6207
Letter
Organic Letters Scheme 3. Thioimidazole Substrate Scopea
Figure 1. Regiodivergent sulfenoamination.
a highly temperature dependent diastereoselectivity outcome (Scheme 4a). More specifically, at lower temperature, the cis Scheme 4. Mechanistic Studies and Proposed Mechanism
a
Standard reaction conditions. The regioisomeric ratios are based on crude NMR. bReported yields are an inseperable mixture of both nitrogen addition products; N1:N2 ratios are based on crude NMR. c1 (2.0 equiv, 1.0 mmol), Selectfluor (1.5 equiv) at 50 °C. d50 °C.
S-additions to the alkene structure, however, remained intact with only nitrogen addition to the benzylic position and sulfur to the terminal carbon. Additionally, 2-thioimidazoles were also viable substrates to achieve excellent regioselectivity with a small decrease in the reaction efficiencies (Scheme 3, products 33 and 34). In our previous sulfenoamination studies with thioamide, we observed the opposite outcome in terms of N- and S-additions for styrene derivatives, in which nitrogen was added to the terminal carbons and sulfur was added to the benzylic positions. As such, we wondered if potential regiodivergent sulfenoamination processes could be achieved based on both the halogenation and electrophilic sulfur activation strategies. In this regard, utilization of Selectfluor as a halogen source resulted in the formation of 3, 7, and 12, as the only regioisomeric products. On the other hand, if bromine was used as the halogen source via 1,2-dibromoethylarene, the opposite regioisomers 35−37 could be produced with great selectivity upon treatment with the thiobenzimidazole nucleophile (Figure 1).13 In combination, these two remarkably regioselective sulfenoamination processes constituted highly regiodivergent approaches for this class of heterocycles. Furthermore, the electronic nature of the styrene substrates had minimal influence on the regioisomeric ratios, highlighting the robustness of regiocontrol in these reactions. To address the mechanistic aspects of this reaction, we have considered some of the evidence. First, the formation of product 18 proceeds with the cyclopropane ring remaining intact. These data suggest that pathways leading to radical formation at the benzylic position are less likely, as such pathways generally will result in the cyclopropane ring opening.14 Second, we also chose cis-β-methylstyrene as a starting substrate in this reaction. In this case, we have observed
diastereomeric product is formed as the major diastereomer in 15% yield and 85:15 dr at 0 °C. In contrast, higher temperatures result in the favoring of the trans heterocycle formation, and at 50 °C, the trans isomer is formed in >98:2 ratio. This temperature dependent behavior is consistent with previous studies on the configurational stability studies of the thiiranium ions conducted by Smit et al. and Denmark et al.15 In addition, the regioselectivity of the aliphatic alkenes, in particular of 3,3-dimethylbutene, is not characteristic of thiyl radical addition reactions. Instead, the ability of steric factors to influence regioselectivity is more aligned with a thiiranium ion. Furthermore, NMR studies, by mixing thiobenzimidazole and Selectfluor in deuterated DMF, reveals a new set of fluorine peaks at 38 ppm, characteristic of a sulfur−fluorine bond.16 Taking into account the above-mentioned information, our proposed mechanism for this reaction is outlined in Scheme 4b. Fluorination of thioimidazole by Selectfluor proceeds to the formation of the active sulfur electrophile. The alkene attack on this sulfur electrophile results in the formation of the thiiranium ion. In most cases the thiiranium ion is unstable, equilibration to the open carbocation can occur, and subsequent nucleophile trapping results in product formation. Alternatively, DMF can also participate in the thiiranium ring openning. The ensuing intramolecular cyclization can then preserve the alkene 6206
DOI: 10.1021/acs.orglett.7b03128 Org. Lett. 2017, 19, 6204−6207
Letter
Organic Letters
Wang, H. J. Org. Chem. 2016, 81, 2252. For related intermolecular examples starting with sulfenyl chlorides: (e) Borisov, A. V.; Goncharova, T. V.; Matsulevich, Z. V.; Borisova, G. N.; Osmanov, V. K. Chem. Heterocycl. Compd. 2001, 37, 783. (f) Borisov, A. V.; Osmanov, V. K.; Nikonova, Y. A.; Borisova, G. N.; Matsulevich, Z. V. Chem. Heterocycl. Compd. 2005, 41, 806. (g) Borisov, A. V.; Osmanov, V. K.; Borisova, G. N.; Matsulevich, Z. V.; Fukin, G. K. Mendeleev Commun. 2009, 19, 49. (5) For examples of electrophilic sulfur reagent synthesis from stable sulfur precursors: (a) Jarboe, S. G.; Terrazas, M. S.; Beak, P. J. Org. Chem. 2008, 73, 9627. (b) Iwasaki, M.; Fujii, T.; Yamamoto, A.; Nakajima, K.; Nishihara, Y. Chem. - Asian J. 2014, 9, 58. (c) Li, Y.; Shi, Y.; Huang, Z.-X.; Wu, X.-H.; Xu, P.-F.; Wang, J.-B.; Zhang, Y. Org. Lett. 2011, 13, 1210. (6) (a) Denmark, S. E.; Chi, H. M. J. Org. Chem. 2017, 82, 3826. (b) Denmark, S. E.; Hartmann, E.; Kornfilt, D. J. P.; Wang, H. Nat. Chem. 2014, 6, 1056. (7) Alom, N.-E.; Wu, F.; Li, W. Org. Lett. 2017, 19, 930. (8) For examples of studies on thiiranium ions: (a) Pettitt, D. J.; Helmkamp, G. K. J. Org. Chem. 1963, 28, 2932. (b) Raynolds, P.; Zonnebelt, S.; Bakker, S.; Kellogg, R. M. J. Am. Chem. Soc. 1974, 96, 3146. (c) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1988, 110, 6900. (d) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1991, 113, 6600. (e) Fachini, M.; Lucchini, V.; Modena, G.; Pasi, M.; Pasquato, L. J. Am. Chem. Soc. 1999, 121, 3944. (9) For examples of sulfur−halogen bonds as electrophiles: (a) Wallbaum, J.; Garve, L. K. B.; Jones, P. G.; Werz, D. B. Org. Lett. 2017, 19, 98. (b) Iwasaki, M.; Fujii, T.; Nakajima, K.; Nishihara, Y. Angew. Chem., Int. Ed. 2014, 53, 13880. (c) Hostier, T.; Ferey, V.; Ricci, G.; Pardo, D. G.; Cossy, J. Chem. Commun. 2015, 51, 13898. (10) To the best of our knowledge, there was only one reported multistep synthesis of compound 3: Wagh, S. J.; Tawde, T. S.; Sapre, J. V.; Khose, V. N.; Karnik, A. V. Indian J. Chem-B 2016, 55B, 707. (11) DMF solvates Selectfluor better and can function as a potent Lewis base to participate in the thiiranium ring openning. (12) The trans or cis stereochemical relationship of compounds 13, 14, 19, and 21 were confirmed by NOE studies. The regiochemical relationship of compounds 3, 20, 22, and 35 were also confirmed by NOE studies. Please see Supporting Information for detailed NOE studies. (13) To the best of our knowledge, there was only one reported multi-step synthesis of compound 35: Krasovskii, A. N.; Klyuev, N. A.; Roman, A. B.; Kochergin, P. M.; Dank, E. K. Khim. Geterotsikl. 1983, 942. (14) For a review on free-radical clocks: Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317. (15) (a) Smit, W. A.; Zefirov, N. S.; Bodrikov, I. V.; Krimer, M. Z. Acc. Chem. Res. 1979, 12, 282. (b) Denmark, S. E.; Vogler, T. Chem. Eur. J. 2009, 15, 11737. (c) Denmark, S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem. Soc. 2009, 131, 3490. The Denmark studies have demonstrated that olefin-to-olefin transfer processes of chiral thiiraniums are highly stereospecif ic with respect to the olefin stereochemistry. It is unlikely that the olefin starting material will racemize based on these studies; therefore, configurational instability of the thiiranium through open carbocation at higher temperature provides the best explanation for the stereoerosion observed here. In addition, the inherent sulfenium structures also play a vital role in their participation in olefin-to-olefin transfer processes and configurational stability. (16) Experimental details of the NMR and cis-b-methylstyrene diastereoselectivity studies are included in the Supporting Information.
stereochemistry in the product, as evidenced in the cis-βmethylstyrene case at lower temperature. In conclusion, we have developed a highly regio- and stereoselective sulfenoamination reaction of alkenes. A broad range of alkene and thioimidazole structures are compatible in this reaction protocol. The stable sulfur reagent can be used for in situ generation of the electrophilic sulfur source. Moreover, we have observed an interesting temperature dependent equilibrium between the thiiranium ion and the open carbocation species. In addition, we have also developed a highly regiodivergent approach to this sulfenoamination reaction utilizing alternative halogenation chemistry. Finally, this modular and practical synthetic approach will enable the generation of exotic heterocyclic motifs for important biological studies.
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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.7b03128. Experimental procedure and characterization data of the products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Wei Li: 0000-0001-8524-217X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the University of Toledo for a startup grant and a grant from the Summer Research Awards and Fellowship Programs. We also thank Dr. Zachary A. Buchan (Dow AgroSciences) and Prof. John Montgomery (University of Michigan) for helpful discussions. We thank Dr. Yong W. Kim (University of Toledo) for NMR assistance.
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REFERENCES
(1) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed.; Springer: New York, 2007; Vol. 1, pp 473−569. For a recent review on challenges and perspectives on electrophilic activation of alkenes: (b) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938. (2) For a review on the importance and frequent appearances of nitrogen and sulfur atoms in pharmaceuticals: Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257. (3) (a) Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 8915. (b) Li, L.; Li, Z.; Huang, D.; Wang, H.; Shi, Y. RSC Adv. 2013, 3, 4523. For a recent example of an intramolecular sulfenoamination reaction by hypervalent iodine activation: (c) Mizar, P.; Niebuhr, R.; Hutchings, M.; Farooq, U.; Wirth, T. Chem. - Eur. J. 2016, 22, 1614. (4) (a) For intermolecular examples of sulfenoamination with electrophilic sulfur activation: Liu, T.; Tian, J.; Gao, W.-C.; Chang, H.H.; Liu, Q.; Li, X.; Wei, W.-L. Org. Biomol. Chem. 2017, 15, 5983. (b) Wang, D.; Yan, Z.; Xie, Q.; Zhang, R.; Lin, S.; Wang, Y. Org. Biomol. Chem. 2017, 15, 1998. For intermolecular examples of sulfenoamination with halogenation: (c) Zheng, Y.; He, Y.; Rong, G.; Zhang, X.; Weng, Y.; Dong, K.; Xu, X.; Mao, J. Org. Lett. 2015, 17, 5444. (d) Cui, H.; Liu, X.; Wei, W.; Yang, D.; He, C.; Zhang, T.; 6207
DOI: 10.1021/acs.orglett.7b03128 Org. Lett. 2017, 19, 6204−6207
