Letter pubs.acs.org/OrgLett
Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the Bench-Stable Solid Reagent (Me4N)SCF3 Thomas Scattolin, Alexander Klein, and Franziska Schoenebeck* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
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S Supporting Information *
ABSTRACT: A highly efficient, selective, and rapid transformation of primary amines and diamines to isothiocyanates and cyclic thioureas is disclosed. As opposed to established approaches that employ toxic or volatile electrophilic liquids and require reaction control (i.e., slow addition, cooling), this protocol utilizes the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is characterized by operational simplicity, high speed, efficiency, high functional group tolerance, and late-stage applicability. The byproducts are solids, allowing isolation of the target compounds by filtration.
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By contrast, this report describes the reaction of a solid, formally nucleophilic “CS” source [i.e., (Me4N)SCF3] with primary amines to generate a range of isothiocyanates in a selective manner. The bench-stable and easily accessible (Me4N)SCF3 salt has recently found widespread applications in the transition-metalcatalyzed trifluoromethylthiolation of aryl (pseudo)halides.8,9 As part of our activities in this area,9 we recently encountered the unexpected direct reactivity of secondary amines with (Me4N)SCF3 to generate thiocarbamoyl fluorides. Capitalizing on the rapid access to this valuable intermediate, we were able to generate a range of R2N−CF3 compounds through further reaction with AgF.10 While our efforts to fully elucidate the mechanism are still ongoing, a notable reactivity feature of (Me4N)SCF3 is the unique selectivity pattern for “N−H” functionality, leaving otherwise more nucleophilic sites, such as, for example, tertiary amines, heterocycles, or alkoxides, that lack a proton untouched.10 As this selectivity contrasts the established nucleophile/electrophile reactivity paradigm, we envisioned that the (Me4N)SCF3 salt should have wider synthetic potential, in particular for late-stage synthetic applications. This report documents our investigation with primary amines. We observed that the addition of the solid (Me4N)SCF3 in a single portion to a solution of aniline and the mild base NEt3 in DCM at room temperature led to the direct and nearquantitative formation of isothiocyanate 3 (illustrated in Scheme 1). Notably, all side species generated in the transformation were salts (tetramethylammonium bifluoride and triethylammonium fluoride) and precipitated as solids upon addition of low polarity solvents (e.g., hexane or pentane) at the end of the reaction, which allowed the isolation of the
sothiocyanates are valuable and ubiquitous building blocks in natural product synthesis, in materials chemistry, in the pharmaceutical arena, and more generally in synthesis.1 Applications range from synthetic intermediates en route to heterocycles, to food additives and compounds of medicinal importance.2 Synthetic access to isothiocyanates is realized primarily through the reaction of primary amines with a highly electrophilic “CS” source, such as carbon disulfide,3 thiophosgene,4,5 or related thiocarbonyl transfer agents (see Figure 1), e.g. thiocarbonyldiimidazole and dipyridylthiono-
Figure 1. General approaches vs our strategy.
carbonate (DPT).6 Despite the arsenal of available reagents, challenges still remain. For example, the commonly used thiophosgene (SCCl2) is a toxic liquid that reacts highly exothermically, requiring careful control of temperature and addition rate. Carbon disulfide (CS2), a highly flammable and volatile liquid, requires stoichiometric coreagents, such as Boc2O, triphosgene, cyanuric chloride, DCC, strong acids or bases, or needs an elevated reaction temperature.4,7 Aside from safety aspects in the general handling of these compounds, their instability and reactivity patterns can also be disadvantageous. For example, low functional group tolerance or selectivity issues may arise as a consequence of their highly electrophilic properties, particularly when applied to the synthesis of densely functionalized compounds, i.e. late-stage synthetic applications. © 2017 American Chemical Society
Received: March 8, 2017 Published: March 30, 2017 1831
DOI: 10.1021/acs.orglett.7b00689 Org. Lett. 2017, 19, 1831−1833
Letter
Organic Letters Scheme 1. Scope in the Synthesis of R−NCSa
substituent. This includes ortho-keto (2), -nitrile (9), and -methoxy (10) functionalities and even the bulky tert-butyl group (7). Additional valuable functional groups, such as nitro (5), thioether (8), halogens (11), ester (16 and 19), and tertiary amine (15), were also shown to be well tolerated, and electron-deficient amines that otherwise react sluggishly by established methods proved to be efficiently transformed also. Moreover, the heterocyclic isothiocyanates (12 and 13) could be synthesized in high yields (75% to 99%). To demonstrate the larger-scale applicability of the methodology, we synthesized 16 on a 10 mmol scale (1.78 g). The solid (Me4N)SCF3 reagent was added in one portion at room temperature also at larger scale. There was no significant warming of the mixture and no need for external cooling and reaction control, as would otherwise be required for alternative highly electrophilic reagents, such as thiophosgene. As a further test of the applicability of this methodology in the synthesis of more complex molecules and pharmaceutical applications, several important drug molecules and medicinally privileged heterocycles were also examined (22−25, Figure 2).
as
Conditions: Amine (0.2 mmol), (Me4N)SCF3 (39 mg, 0.22 mmol), Et3N (42 μL, 0.3 mmol), DCM (1.5 mL). bFull conversion was observed in 15 h.
R−NCS upon simple filtration. Our further explorations showed that not only DCM but also a wide range of alternative solvents could be utilized for these reactions, such as toluene, EtOAc, acetone, THF, Me-THF, MeCN, MTBE, and CPME. The transformations were equally fast and efficient in these media. As such, the method appears to be highly practical, using an easy-to-handle solid as the “CS” source, so circumventing the need for cooling, slow addition, or purification from stoichiometric coreagents or byproducts. Moreover, the (Me4N)SCF3 reagent is characterized by high stability. It is completely stable as a solid and also in solution. Our preliminary mechanistic data suggest that there is no spontaneous liberation of the potentially reactive electrophile, SCF2.11 Instead, our in situ NMR spectroscopic studies suggest that the reagent remains unchanged in solution until addition of the reactive “N−H” substrate, which results in the direct and rapid formation of R−NCS and salt byproducts. We next set out to explore the full scope of this transformation. A wide range of aliphatic and aromatic primary amines were efficiently transformed with (Me4N)SCF3, yielding the corresponding R−NCS compounds in excellent yields (see Scheme 1). The protocol proved to be compatible with bulky aliphatic amines (e.g., adamantyl 17 or tert-butyl 20), electron-rich or -deficient aromatic amines, and a wide range of functional groups. The efficiency was not influenced by the relative positioning of the amine group to additional substituents on the aromatic ring: ortho-, meta-, and para-substituents were fully tolerated, regardless of the electronic or steric nature of the
Figure 2. Synthesis of pharmaceutical analogues using analogous conditions to Scheme 1.
Once again, the transformations were found to be highly effective, regardless of the molecular complexity. Notably, there was distinct selectivity for the primary amine, leaving sensitive (dihydropyridine 24) and alternative nucleophilic moieties (such as pyridazine in 23 and the tertiary amine in 25) completely untouched. To further probe the reactivity of (Me4N)SCF3 relative to established electrophilic “CS” sources, we undertook a comparative examination of thiophosgene vs (NMe4)SCF3 for their ability to discriminate between primary and secondary amine sites by reaction with N-methyl-1,3-diaminopropane (see Scheme 2). While thiophosgene generated a complex mixture of polymeric material under analogous conditions, the welldefined unsymmetrical cyclic thiourea 31 (83%) was formed with our method. Such cyclic, unsymmetrical thioureas are used as antiatherosclerotic agents (i.e., for declogging of arteries),12 as crucial synthetic intermediates en route to pharmaceutically relevant molecules,13 as ligands for metals,14 or as precursors to access N-heterocyclic carbenes via reduction.15 They are traditionally made with CS2 under strongly acidic conditions and/or high temperature.16 Thus, our method constitutes a significant advance, being mild, safe, and convenient. We present several more examples in Scheme 2, including five- and six-membered rings. A notable highlight is the synthesis of 29 in 90% yield, a relative of a key intermediate toward Dabigatran 1832
DOI: 10.1021/acs.orglett.7b00689 Org. Lett. 2017, 19, 1831−1833
Organic Letters
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Scheme 2. Scope of Unsymmetrical Cyclic Thioureas (1) and Test Reaction with Thiophosgene (2)a
etexilate,17 showcasing the utility of the reagent for the synthesis of pharmaceutically relevant molecules. In summary, a convenient, operationally simple, and comparably safe method to access isothiocyanates and unsymmetrical cyclic thioureas from the bench-stable solid (Me4N)SCF3 and primary amines has been disclosed herein. The method is characterized by high speed, selectivity, generality, functional group tolerance, and ease of purification (filtration). As opposed to traditional reagents to access these compound classes, there is no requirement for external cooling or reaction control (such as slow addition), allowing addition of the solid reagent (Me4N)SCF3 at room temperature in one portion, even at larger scale (for up to 10 mmol, >1 g demonstrated).
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00689. Experimental procedures and spectroscopic characterization data, 1H and 13C NMR spectra of the new compounds (PDF)
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REFERENCES
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a Conditions: Diamine (0.2 mmol), (Me4N)SCF3 (39 mg, 0.22 mmol), Et3N (42 μL, 0.3 mmol), DCM (1.5 mL).
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Franziska Schoenebeck: 0000-0003-0047-0929 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the RWTH Aachen University and the MIWF NRW. 1833
DOI: 10.1021/acs.orglett.7b00689 Org. Lett. 2017, 19, 1831−1833
