Regioselective Synthesis of Fluorosulfonyl 1, 2, 3-Triazoles from

Jun 15, 2018 - A regioselective metal-free preparation of 4-fluorosulfonyl 1,2,3-triazoles from organic azides and a hitherto underexplored bromovinyl...
0 downloads 0 Views 1MB Size
Download PDF
Letter Cite This: Org. Lett. 2018, 20, 3749−3752

pubs.acs.org/OrgLett

Regioselective Synthesis of Fluorosulfonyl 1,2,3-Triazoles from Bromovinylsulfonyl Fluoride Joice Thomas and Valery V. Fokin* The Bridge@USC and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, United States

Downloaded via UNIV OF BRITISH COLUMBIA on July 6, 2018 at 11:40:36 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A regioselective metal-free preparation of 4-fluorosulfonyl 1,2,3-triazoles from organic azides and a hitherto underexplored bromovinylsulfonyl fluoride building block is described. This reaction is very general and was extended to the synthesis of various sulfonates, sulfonamides, and sulfonic acid derivatives of triazoles and other azole heterocycles which would otherwise be difficult to access by existing methods. he chemistry of organic sulfur(VI) fluoride derivatives has attracted interest owing to the stability and selective reactivity of −SO2F.1 The unique features that distinguish sulfur(VI) oxofluoride derivatives from their other halogenated congeners, such as −SO2Cl, are higher resistance to hydrolysis under basic and acidic conditions, the lack of radical and redox side reactions which lead to oxidations and halogenations, and selective reactivity with nucleophiles, including properly activated silyl ether precursors. The latter sulfur(VI) fluoride exchange (SuFEx) reactions produce sulfates and sulfonates along with a thermodynamically stable silyl fluoride byproduct.1a These characteristics make sulfur(VI) oxofluoride derivatives privileged entities for a variety of biological applications, including the synthesis of pharmaceutically active agents,2 covalent modifiers of biomacromolecules,3 and fluorinating4 and 18F-radiolabeling5 reagents (Figure 1). They also serve as bench-stable synthetic

T

aromatic sulfate- or sulfonate-based polymeric materials as well as in selective postpolymerization modification.7 After the discovery of the copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction, 1,4-disubstituted 1,2,3-triazole heterocycles have found many uses in molecular sciences ranging from medicinal chemistry to materials applications.8 However, fluorosulfonyl- and sulfonate-functionalized triazoles are conspicuously missing from the repertoire of these heterocycles. A cursory survey of the literature revealed only two reports dealing with the synthesis of triazole rings decorated with sulfonamide derivatives.9 Unfortunately, the reported syntheses give the product in low overall yield (≤10%) and involve several unselective steps that include alkylation of NH-triazoles and the involvement of unstable sulfonyl chloride intermediates (eq 1). These steps significantly limit the utility of this pathway

Figure 1. Sulfonyl fluoride containing biological probes and reagents.

for investigating structure−activity relationship studies and further exploring the reactivity of these novel compounds.

intermediates in a plethora of chemical transformations, such as the preparation of sulfones, sulfonamides, sulfonic esters, sulfonic acids, and other sulfur(VI) derivatives.1,6 In this context, our group and others have successfully employed sulfur(VI) oxofluoride derivatives as synthons for the generation of stable © 2018 American Chemical Society

Received: April 25, 2018 Published: June 15, 2018 3749

DOI: 10.1021/acs.orglett.8b01309 Org. Lett. 2018, 20, 3749−3752

Letter

Organic Letters Herein, we report a new and general protocol for the synthesis of bench-stable fluorosulfonyl 1,2,3-triazoles which is broadly applicable to the construction of densely functionalized sulfur(VI) derivatives of these heterocycles (eq 2). Specifically, we envisioned that bromoethenylsulfonyl fluoride (Br-ESF) could serve as a stable synthetic equivalent of the synthetically inaccessible ethynylsulfonyl fluoride.10 We anticipated that a cycloaddition reaction between organic azides and Br-ESF would install the required −SO2F functionality regiospecifically at the C4 position of the 1,2,3-triazole heterocycle after aromatization by spontaneous elimination of HBr.11 Although Br-ESF has been known since 1985,10 it has not proven popular with in the synthetic community, likely because its efficient preparation has not been described until our work. We have now devised conditions for its large-scale preparation which allow the isolation of this useful reagent in two steps via the photobromination of ethenesulfonyl fluoride 1 followed by a dehydrobromination of the resulting dibromoethanesulfonyl fluoride 2 (eq 3). Of particular note, we found

that the addition of bromine to the double bond under conventional conditions required 48 h for complete conversion, whereas illumination with a simple 40-W bulb reduced the reaction time to only 10 h. This protocol can be employed for the preparation of Br-ESF on a multigram scale (68 g) in overall excellent yield. We examined the reactivity of Br-ESF 3 with benzyl azide 4a in the presence and absence of various bases. We found that the reaction of 3 and 4a (1.4:1, 1 M in DMF) at 50 °C consistently provided the desired product in high yield (see the Supporting Information).10 Thus, triazole 5a was obtained after 14 h in 89% isolated yield with a regioselectivity of >99%. The presence of the strongly electron-withdrawing −SO2F in the dipolarophile 3 results in exclusive attack at the partially positively charged β-carbon of the Br-ESF, providing the C4-fluorosulfonylated triazole as the only product. The multigram preparation of the triazole 5a confirmed the scalability of the process (eq 4).

Figure 2. Sulfonyl triazoles from obtained from Br-ESF and organic azides. RReaction conditions: (a) 3 (1.4 mmol), 4 (1 mmol), 50 °C, 14 h, isolated yield; (b) 24 h; (c) 3 (1.4 mmol), 4l (0.5 mmol), 50 °C, 40 h; (d) 3 (1.4 mmol), 4m (0.5 mmol), 50 °C, 24 h; (e) 3 (20 mmol), 4n and 4o (10 mmol), 24 h, 80 °C; (f) 3 (2 mmol), 4p−s (1 mmol), 24 h, 80 °C; (g) 3 (0.7 mmol), 4t (0.5 mmol), 24 h, 80 °C; (h) 3 (1.1 mmol), 4u (0.5 mmol), 40 h, 80 °C.

this transformation without compromising the overall yield. Triazoles containing a chiral center (5j and 5k) were also accessed in high yields. Moreover, this protocol succeeded with bifunctional building blocks which gave the bis(triazole) derivatives 5l and 5m in excellent yield, even for the sterically encumbered bis-azido derivative of thiabicyclo[3.3.1]nonane 4l. These reactions were slightly slower but still furnished the desired products in good yield. Aromatic azides (4n−s) engaged in the reaction equally well, and methoxy-, bromo-, ester-, phenyl-, and trifluoromethylsubstituted products were obtained in generally good to excellent yield (5o−r). The reactions were not affected by the steric hindrance imparted by the methyl groups at the ortho positions of the 2-azidomesitylene (5s). In general, aromatic azides required an excess of Br-ESF (2 equiv) and higher temperature and longer reaction time (80 °C, 24 h) as compared to aliphatic azides. The identities of 1,4-disubstituted 1,2,3-triazoles 5b and 5q were unambiguously confirmed by single-crystal X-ray crystallographic analysis. Complex bioactive molecules and natural products functionalized with azido groups were converted to the unique triazolecontaining natural products decorated with a clickable −SO2F group, which could later be utilized for other applications. For example, an antiviral drug azidothymidine (AZT) was readily converted to the corresponding −SO2F-functionalized triazole 5t as the sole product. Also, applying this approach to dihydrocholesterol with the azido group at the C3 position of the A ring delivered the expected product 5u.

The exceptional stability of the fluorosulfonyl group makes it easy to isolate these products using silica gel chromatography. They can be stored at room temperature with no detectable decomposition for weeks. The resistance of the −SO2F group toward hydrolysis was further assessed by stirring the triazole products in water at room temperature while monitoring reaction progress by GC−MS. Remarkably, no degradation was observed even after 5 days. The scope of the reaction is illustrated by the examples shown in Figure 2. All products were obtained with exquisite regioselectivity. Thus, aliphatic azides (5a−m) containing various functional groups such as urea (5c) and alcohols (5d) were compatible with this process. Coumarin and piperazine derivatives cleanly delivered the expected products 5e and 5f in high yields. The sterically encumbered adamantane 4g, fluorene 4h, and succinimide 4i derivatives of azides readily engaged in 3750

DOI: 10.1021/acs.orglett.8b01309 Org. Lett. 2018, 20, 3749−3752

Letter

Organic Letters Azides containing acid-sensitive groups also participated in the reaction when an equivalent of a non-nucleophilic base such as 2,6-di-tert-butyl-4-methylpyridine was added (Figure 3).

Figure 3. Reactions of azides containing acid-sensitive functional groups.

Thus, triazoles 5v and 5w were obtained in good yields. Gratifyingly, these conditions were also amenable for the functionalization of a BODIPY dye with a fluorosulfonyl group (product 5x), which is useful in fluorescence imaging and bioconjugation applications.13 On the other hand, organic azides containing nucleophilic nitrogens failed to react, likely due to the decomposition of the Br-ESF. To explore postsynthetic modifications of sulfonyl triazoles, we explored the utility of the SuFEx reaction for the incorporation of sulfonate derivatives into the triazole ring (Figure 4).

Figure 5. Synthesis of 4-sulfonamidotriazoles.

triazole nucleus with oleum is challenging due to the protonation of the N2/N3 atoms. Basic hydrolysis of −SO2F group overcomes this limitation. We were pleased to isolate the first example of a sulfonic acid salt of triazole compound 14 in excellent yield (eq 5).

The versatility of Br-ESF as the ethynylsulfonyl fluoride synthon was demonstrated by the synthesis of another heterocycle, 5-fluorosulfonyl isoxazole 17 (65% isolated yield), via 1,3-dipolar cycloaddition reaction of 3 and in situ generated nitrile oxide 16. The subsequent SuFEx derivatization delivered the sulfone derivative of isoxazole 18 in 78% yield (eq 6).

Figure 4. Synthesis of arylsulfonates using the SuFEx reaction.

When 4-(tert-butyldimethylsiloxy)toluene and 5n was used as the coupling partner and (n-Bu)4N+HF2− as the catalyst, substitution at the S(VI)−F bond yielded the sulfonate product 7a in excellent yield. In a similar fashion, naturally occurring estrone was readily converted to triazolyl sulfonate 7b. The bisfunctionalized phenol blocks such as bisphenol A and methyl 3,5-dihydroxybenzoate-derived silyl ethers smoothly delivered the corresponding bis-sulfonate products 7c and 7d. Silyl enol ethers 8a and 8b reacted in the presence of the catalytic Et4N+F−12 to provide 9a and 9b in satisfactory yield. Next, we examined the synthesis of a range of sulfonamide moieties in the 1,2,3-triazole ring (Figure 5). These stable pharmacophores are difficult to obtain by other means.6 Reactions of both primary and secondary amines furnished the desired sulfonamides in good yield (11a−c). Similarly, imidazole and ammonia were also competent coupling partners (11d,e). Natural products and their derivatives containing primary amines, such as optically active leelamine, L-tyrosine tert-butyl ester, and aminosteroid funtamine were successfully transformed into the corresponding sulfonamide derivatives 11f−h. N-(Trimethylsilyl)pyrrolidone 12a and as oxazolidinones 12b reacted with 5o in the bifluoride-catalyzed SuFEx reaction to furnish the desired sulfonamide products 13a and 13b in good yield. The electrophilicity of the −SO2F group can be utilized to obtain sulfonate salts of 1,2,3-triazoles. Direct sulfonation of the

In summary, a very efficient and experimentally convenient synthetic protocol for the preparation of the previously elusive sulfonyl fluoride-functionalized 1,2,3-triazoles from Br-ESF and organic azides is now available. The reaction is performed under simple conditions, is readily scaled up, and does not require metal catalysts. It is high-yielding and highly regioselective. Postfunctionalization of triazoles adorned with an electrophilic yet sufficiently stable fluorosulfonyl group provides convenient access to various sufur(VI) derivatives of 1,2,3-triazoles, which were previously inaccessible. Further exploration of this reactivity and its applications is currently underway in our laboratories.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01309. Experimental details and analytical data of the new compounds (PDF) Accession Codes

CCDC 1840629−1840630 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by 3751

DOI: 10.1021/acs.orglett.8b01309 Org. Lett. 2018, 20, 3749−3752

Letter

Organic Letters

(8) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (c) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013, 113, 4905. (9) (a) Cioffi, C. L.; Liu, S.; Wolf, M. A.; Guzzo, P. R.; Sadalapure, K.; Parthasarathy, V.; Loong, D. T. J.; Maeng, J.-H.; Carulli, E.; Fang, X.; Karunakaran, K.; Matta, L.; Choo, S. H.; Panduga, S.; Buckle, R. N.; Davis, N. R.; Sakwa, S. A.; Gupta, P.; Sargent, B. J.; Moore, N. A.; Luche, M. M.; Carr, G. J.; Khmelnitsky, Y. L.; Ismail, J.; Chung, M.; Bai, M.; Leong, W. Y.; Sachdev, N.; Swaminathan, S.; Mhyre, A. J. J. Med. Chem. 2016, 59, 8473. (b) Hunt, H. J.; Belanoff, J. K.; Walters, I.; Gourdet, B.; Thomas, J.; Barton, N.; Unitt, J.; Phillips, T.; Swift, D.; Eaton, E. J. Med. Chem. 2017, 60, 3405. (10) (a) Champseix, A.; Chanet, J.; Etienne, A.; Le Berre, A.; Masson, J. C.; Napierala, C.; Vessiere, R. Bull. Soc. Chim. Fr. 1985, 463. (b) Vessière, R.; Chanet-Ray, J.; Zéroual, A. Heterocycles 1987, 26, 101. (c) Baxter, N. J.; Rigoreau, L. J. M.; Laws, A. P.; Page, M. I. J. Am. Chem. Soc. 2000, 122, 3375. (11) (a) Thomas, J.; John, J.; Parekh, N.; Dehaen, W. Angew. Chem. 2014, 126, 10319. (b) John, J.; Thomas, J.; Dehaen, W. Chem. Commun. 2015, 51, 10797. (12) Hirsch, E.; Hunig, S.; Reißig, H.-U. Chem. Ber. 1982, 115, 399. (13) Kowada, T.; Maeda, H.; Kikuchi, K. Chem. Soc. Rev. 2015, 44, 4953.

emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Joice Thomas: 0000-0001-5517-4663 Valery V. Fokin: 0000-0001-7323-2177 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE-1660373). REFERENCES

(1) (a) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2014, 53, 9430. (b) Narayanan, A.; Jones, L. H. Chem. Sci. 2015, 6, 2650. (c) Dondoni, A.; Marra, A. Org. Biomol. Chem. 2017, 15, 1549. (d) Yatvin, J.; Brooks, K.; Locklin. Chem. - Eur. J. 2016, 22, 16348. (2) (a) Nelson, H. M.; Williams, B. D.; Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 3213. (b) James, G. T. Anal. Biochem. 1978, 86, 574. (c) Lively, M. O.; Powers, J. C. Biochim. Biophys. Acta 1978, 525, 171. (d) Colman, R. F. Annu. Rev. Biochem. 1983, 52, 67. (3) (a) Grimster, N. P.; Connelly, S.; Baranczak, A.; Dong, J.; Krasnova, L. B.; Sharpless, K. B.; Powers, E. T.; Wilson, I. A.; Kelly, J. W. J. Am. Chem. Soc. 2013, 135, 5656. (b) Baranczak, A.; Liu, Y.; Connelly, S.; Du, W. G. H.; Greiner, E. R.; Genereux, J. C.; Wiseman, R. L.; Eisele, Y. S.; Bradbury, N. C.; Dong, J.; Noodleman, L.; Sharpless, K. B.; Wilson, I. A.; Encalada, S. E.; Kelly, J. W. J. Am. Chem. Soc. 2015, 137, 7404. (c) Chen, W.; Dong, J.; Li, S.; Liu, Y.; Wang, Y.; Yoon, L.; Wu, P.; Sharpless, K. B.; Kelly, J. W. Angew. Chem., Int. Ed. 2016, 55, 1835. (d) Chen, W.; Dong, J.; Plate, L.; Mortenson, D. E.; Brighty, G. J.; Li, S.; Liu, Y.; Galmozzi, A.; Lee, P. S.; Hulce, J. J.; Cravatt, B. F.; Saez, E.; Powers, E. T.; Wilson, I. A.; Sharpless, K. B.; Kelly, J. W. J. Am. Chem. Soc. 2016, 138, 7353. (e) Yatvin, J.; Brooks, K.; Locklin, J. Angew. Chem., Int. Ed. 2015, 54, 13370. (f) Gushwa, N. N.; Kang, S.; Chen, J.; Taunton, J. J. Am. Chem. Soc. 2012, 134, 20214. (g) Hett, E. C.; Xu, H.; Geoghegan, K. F.; Gopalsamy, A.; Kyne, R. E.; Menard, C. A.; Narayanan, A.; Parikh, M. D.; Liu, S.; Roberts, L.; Robinson, R. P.; Tones, M. A.; Jones, L. H. ACS Chem. Biol. 2015, 10, 1094. (4) Nielsen, M. K.; Ugaz, C. R.; Li, W.; Doyle, A. G. J. Am. Chem. Soc. 2015, 137, 9571. (5) (a) Inkster, J. A. H.; Liu, K.; Ait-Mohand, S.; Schaffer, P.; Guerin, B.; Ruth, T. J.; Storr, T. Chem. - Eur. J. 2012, 18, 11079. (b) Matesic, L.; Wyatt, N. A.; Fraser, B. H.; Roberts, M. P.; Pham, T. Q.; Greguric, I. J. Org. Chem. 2013, 78, 11262. (6) (a) Qin, H.-L.; Zheng, Q.; Bare, G. A. L.; Wu, P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2016, 55, 14155. (b) Brooks, K.; Yatvin, J.; McNitt, C. D.; Reese, R. A.; Jung, C.; Popik, V. V.; Locklin, J. Langmuir 2016, 32, 6600. (c) Chinthakindi, P. K.; Govender, K. B.; Kumar, A. S.; Kruger, H. G.; Govender, T.; Naicker, T.; Arvidsson, P. I. Org. Lett. 2017, 19, 480. (7) (a) Dong, J.; Sharpless, K. B.; Kwisnek, L.; Oakdale, J. S.; Fokin, V. V. Angew. Chem., Int. Ed. 2014, 53, 9466. (b) Oakdale, J. S.; Kwisnek, L.; Fokin, V. V. Macromolecules 2016, 49, 4473. (c) Gao, B.; Zhang, L.; Zheng, Q.; Zhou, F.; Klivansky, L. M.; Lu, J.; Liu, Y.; Dong, J.; Wu, P.; Sharpless, K. B. Nat. Chem. 2017, 9, 1083. (d) Wang, H.; Zhou, F.; Ren, G.; Zheng, Q.; Chen, H.; Gao, B.; Klivansky, L.; Liu, Y.; Wu, B.; Xu, Q.; Lu, J.; Sharpless, K. B.; Wu, P. Angew. Chem., Int. Ed. 2017, 56, 11203. 3752

DOI: 10.1021/acs.orglett.8b01309 Org. Lett. 2018, 20, 3749−3752