Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
In Situ Activation of Disulfides for Multicomponent Reactions with Isocyanides and a Broad Range of Nucleophiles Xiaofang Lei,† Yuanyuan Wang,† Erkang Fan,‡ and Zhihua Sun*,† †
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science 333 Longteng Road, Shanghai 201620, China ‡ Department of Biochemistry, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States
Org. Lett. Downloaded from pubs.acs.org by MIDWESTERN UNIV on 02/11/19. For personal use only.
S Supporting Information *
ABSTRACT: Activation of disulfides with N-halogen succinimide in the presence of TEMPO allows insertion reaction by an isocyanide, the product of which can further accept a wide range of nucleophiles for the generation of isothioureas and related molecular moieties. This new procedure overcomes previous methods that accept essentially only aryl amines as the third nucleophilic component. The diverse nucleophiles usable in our new protocol make this approach a general method for de novo synthesis of many S-containing heterocycles.
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some heterocyclic compounds such as those S-alkyl or S-aryl sulfanyl substituted [1,2,4]triazoles found in compounds 1 or 2, fused rings in compound 5, or aminothiazoles in compound 6 can be a challenge. For example, large-scale synthesis of compound 1 requires the handling of 4-aryl-[1,2,4]triazole-3thiol-related intermediates,4 which was reported to have toxic effects on skin, eyes, and the respiratory track.5 It is therefore very desirable to develop a general and efficient synthetic methodology for the construction of an isothiourea moiety in many different forms. In this regard, we aim to develop such synthetic methodology based on a multicomponent reaction of isocyanides with an electrophilic sulfur center and a broad range of nucleophiles. While three-component reactions involving isocyanides and electrophilic sulfur centers have been reported by us6 and the Maes group,7 both published procedures (Scheme 1) have the limitation that generally the third nucleophilic component has to be aromatic amines or special aliphatic amines with low pKa. Using our reported protocol, a broader range of nucleophiles are acceptable only when the reaction is carried out in an intramolecular fashion. As a consequence, our sulfenic acid based protocol is more useful in the construction of heterocycles with fused ring systems.6 In order to expand the application of such three-component reactions, we thought to change the reaction pathway so that the limitations on the nucleophilic component can be overcome. Our previously reported method was thought to proceed through isocyanide addition to sulfenic acid to form an iminomethylene sulfornium intermediate after loss of water, which allows further reaction with a nucleophile (Scheme 1).6
he isothiourea moiety is an important feature present in many small molecules used in chemical and biological applications. Figure 1 shows select examples of molecules (compounds 1−7) that contain the isothiourea moiety in various forms as an approved drug,1 as potent inhibitors of biological targets/pathways,2 or as a chiral catalyst.3 While synthetic procedures for a standard isothiourea such as that present in compound 3 are straightforward,2b synthesis of
Figure 1. Select examples of molecules that contain the isothiourea moiety. © XXXX American Chemical Society
Received: January 22, 2019
A
DOI: 10.1021/acs.orglett.9b00275 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 1. Comparison of the Present Reaction Pathway That Can Accept a Wide Variety of Nucleophiles to Earlier Reports with Limited Aryl Amine Nucleophiles
Table 1. Using a Model Reaction To Explore Reaction Conditions
entry
initiator
oxidant
solvent
ratio (a/b/c/d/ e)
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12
TEMPO TEMPO TEMPO TEMPO TEMPO TEMPO TEMPO none AIBN (60 °C) none (60 °C) BPO (40 °C) TEMPO
NCS NCS NCS NCS NCS NCS NBS NCS NCS NCS NCS NCS
toluene THF DMF CH3CN DCM DCE DCM DCM DCE DCE DCM DCM
1/0.2/2/2/2 1/0.2/2/2/2 1/0.2/2/2/2 1/0.2/2/2/2 1/0.2/2/2/2 1/0.2/2/2/2 1/0.2/2/2/2 1/0/2/2/2 1/0.2/2/2/2 1/0/2/2/2 1/0.2/2/2/2 1/0.2/1/2/2
trace 83 45 75 85 82 55 none 82 none 14 58a
a
We reasoned that if we start with a corresponding sulfenyl halide instead of sulfenic acid, one may expect that an isocyanide can be inserted to form a S-substituted thiomethylimidoyl halide similar to that of isocyanide insertion to an acyl halide.8 Reactions of isocyanides with sulfenyl halides followed by intramolecular trapping or solvent-assisted transformation were reported before.9 If we can identify conditions compatible with a third nucleophile, potentially this reaction pathway can accept a wide variety of nucleophiles for multicomponent transformations (Scheme 1). Preparation of sulfenyl halides was well documented through reaction of N-halogen succinimide or halogen with thiols10 or sulfuryl halides with disulfides.11 For ease of starting material access and consideration of compatibility to multicomponent reaction settings, we sought to achieve the preparation of sulfenyl halides using disulfides and N-halogen succinimide. We found that in the presence of 0.2 equiv of TEMPO, sulfenyl chloride can be readily obtained with a disulfide and 2 equiv of NCS. We then used this condition to explore a model reaction of activating phenyl disulfide with NCS, followed by addition of benzyl isocyanide, and then by addition of aniline as the nucleophile. As shown in Table 1, high yields of the desired final product were obtained in several solvent systems such as THF, DCM, DCE, or acetonitrile, but toluene was not good while DMF produced moderate yield (entries 1−6 in Table 1). Under similar reaction conditions, using NBS was slightly less effective than NCS, giving 55% yield (entry 7). It seems that the generation of sulfenyl halide went through a radical pathway because eliminating TEMPO from the system gave no final product (entry 8) while using a radical initiator AIBN at 60 °C produced the desired product with 82% yield (entry 9 and control reaction omitting AIBN as entry 10). Another radical initiator benzoyl peroxide (BPO) was less effective (14% yield, entry 11). If the reaction indeed goes through a radical pathway, one may expect that not only sulfenyl halide is generated during the reaction but also Nsulfenyl succinimide may also be formed (see Scheme 1) and only 1 equiv of NCS or NBS is necessary to carry out the reaction. A reaction using 1 equiv of NCS was performed, and after 24 h of reaction, more than 50% yield was achieved (entry 12), indicating both sulfenyl halide and N-sulfenyl succinimide were involved in the reaction, although the condition using 2 equiv of NCS is more efficient (entry 5). We have
Reaction time: 24 h.
spectroscopic evidence of both sulfenyl chloride and Nsulfenyl succinimide related intermediates in the reaction mixture (see the Supporting Information). We also found that the isolated N-sulfenyl succinimide can react with benzyl amine to give the final desired product (see the Supporting Information). With the success of the model reaction, we proceeded to explore the scope of tolerance for the various disulfides and the final nucleophiles while keeping the isocyanide constant (benzyl isocyanide). The results are summarized in the following schemes (Schemes 2 and 3). In Scheme 2, the first 12 examples used aniline or substituted anilines as the nucleophile while exploring a range of aryl and alkyl disulfides. In most cases, isolated yields of >70% were achieved for aryl or Scheme 2. Substrate Scope for Reactions of Disulfides with Isocyanides and Nitrogen-Based Nucleophiles
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DOI: 10.1021/acs.orglett.9b00275 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
succinimide. We now can turn our attention to demonstrate the application of our method in the construction of diverse Scontaining heterocycles (particularly single-ring examples) that are important in chemical and biological research. As shown in Table 2, in this preliminary study, we have successfully formed several different S-containing ring systems with readily accessible starting materials and high efficiency.
Scheme 3. Substrate Scope for Reactions of Disulfides with Isocyanides and O-, S-, or C-Based Nucleophiles
Table 2. Construction of Several Important S-Containing Heterocyclic Moieties
a
The disulfide is 1,2-diphenyldisulfane. bThe disulfide is 1,2dibutyldisulfane. cThe nucleophile is sodium methoxide. dThe nucleophile is sodium isopropoxide. eThe nucleophile is sodium trifluoroacetate. fThe nucleophile is thiophenol. gThe nucleophile is phenyl magnesium bromide. hThe nucleophile is 1H-indole. iThe nucleophile is 5-methoxy-1H-indole. jThe nucleophile is 5-bromo-1Hindole. kThe nucleophile is 1-methyl-1H-pyrrole. lThe nucleophile is N-methylaniline. mThe nucleophile is 4-fluoro-N-isopropylaniline. n The ortho-position product was isolated at 18%.
alkyl disulfides while 4-nitrophenyl and 2-pyridyl disulfides gave yields around 53−55% (compound 11 and 14). Then the next eight examples in Scheme 2 explored the use of nonaromatic amines as nucleophiles. It shows that ammonia, alkyl amines, and hydrazines are all good nucleophiles for the intended reactions with 75−86% isolated yields of the final products. These results showed that our new protocol met our goal of overcoming the limitation of using aryl amines as nucleophiles for multicomponent reactions of electrophilic sulfurs and isocyanides. It thus opens up new general methodologies for the de novo construction of S-containing heterocycles (see the later results). Scheme 3 contains examples with non-nitrogen nucleophiles. The first five examples cover oxygen-based nucleophiles in the form of alkoxides. The isolated yields were in the range of 25−62% and in general worse than examples of nitrogenbased nucleophiles as shown in Scheme 2. This indicates that additional work is needed to improve our procedures for reactions with alcohols/alkoxides. On the other hand, PhSH or PhMgBr gave acceptable results with, respectively, 75% and 65% isolated yields and demonstrated the general acceptance of S- or C-based nucleophiles (compounds 33 and 34). Compounds 35−38 shows special indole-based carbon nucleophiles with excellent isolated yields (all >80%), and the result with N-alkyl pyrrole (compound 39, 71% yield) is also good. The last two examples are N-substituted anilines. The reduced reactivity of the aniline nitrogen due to Nsubstitution allows the carbon at the ortho- or para-position to act as a nucleophile for the intended reaction, and good yields were obtained (63−81%, compounds 40 and 41). Examples in the preceding tables demonstrate that our new sulfenyl halide/succinimide route is suitable for a wide range of nucleophiles after isocyanide insertion to the sulfenyl halide/
Because our protocol can use hydrazine as a nucleophile, the first examples in Table 2 attempted to synthesize sulfanylsubstituted [1,2,4]triazoles. In entry 1, the desired triazole final product was obtained in 86% isolated yield. Entry 2 in Table 2 shows an example of synthesizing 2-sulfanyl-substituted imidazole. The final product was obtained in 78% isolated yield. Starting from entry 3, the examples cover compounds with the S atom resides within the ring system (single or fused). In C
DOI: 10.1021/acs.orglett.9b00275 Org. Lett. XXXX, XXX, XXX−XXX
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entry 3, an example of nonaromatic isothiourea ring was shown with 73% isolated yield. Entries 4−6 contain the same core 2amino thiazole ring moiety while altering the 4-position substitution with an alkoxy group (entry 4, 68%), a phenyl group (entry 5, 76%), or an alkyl group bearing additional leaving groups that led to the formation of a fused ring (entry 6, 56%). Finally, entry 7 shows an example for the construction of the benzotetramisole (BTM) moiety present in an important class of organic catalysts with 71% isolated yields. Overall, examples in Table 2 demonstrate that our new multicomponent protocol can serve as a general synthetic method for de novo construction of many important Scontaining heterocycles. We also use this new protocol to synthesize the FDA approved drug lesinurad (Scheme 4). The ester precursor to
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhihua Sun: 0000-0003-2407-6010 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the Science and Technology Commission of Shanghai Municipality (17ZR1412000).
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REFERENCES
(1) (a) Hoy, S. M. Drugs 2016, 76, 509. (b) Burns, C. M.; Wortmann, R. L. Lancet 2011, 377, 165. (c) Girardet, J.-I.; Koh, Y.H.; De La Rosa, M.; Gunic, E.; Hong, Z.; Lang, S.; Kim, H. W. Patent WO 2006/026356, Mar 9, 2006. (2) (a) Kitao, Y.; Kawakami, H.; Matsuo, A. Patent WO 2003/ 048134, Jun 12, 2003. (b) Istyastono, E. P.; Nijmeijer, S.; Lim, H. D.; van de Stolpe, A.; Roumen, L.; Kooistra, A. J.; Vischer, H. F.; de Esch, I. J. P.; Leurs, R.; de Graaf, C. J. Med. Chem. 2011, 54, 8136. (c) Matsuo, A.; Negoro, T.; Seo, T.; Kitao, Y.; Shindo, M.; Segawa, H.; Miyamoto, K. Eur. J. Pharmacol. 2005, 517, 111. (d) Thoma, G.; Streiff, M.; Kovarik, B. J.; Glickman, F.; Wagner, T.; Beerli, C.; Zerwes, H.-G. J. Med. Chem. 2008, 51, 7915. (e) Bonn, P.; Brink, D.; Fägerhag, M. J.; Jurva, U.; Robb, G.; Schnecke, V.; Svensson Hendriksson, A.; Waring, M.; Westerlund, J. C. Bioorg. Med. Chem. Lett. 2012, 22, 7302. (3) (a) Belmessieri, D. L.; Morrill, C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714. (b) West, T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2014, 136, 4476. (c) Joannesse, C.; Johnston, C.; Concellon, P. C.; Simal, C.; Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914. (4) (a) Quart, B. D.; Girardet, J.-I.; Gunic, E.; Yeh, L.-T. Patent WO 2009/070740, Jun 4, 2009. (b) Zamansky, I.; Galvin, G.; Girardet, J.I. Patent WO 2011/085009, July 14, 2011. (c) Gunic, E.; Galvin, G. Patent WO 2014/008295, Jan 9, 2014. (5) Kaplaushenko, A. H. O.; Panasenko, I.; Knish, E. H.; Shcherbina, R. O. Farm. Zh. (Kiev, Ukraine) 2008, No. 2, 67. (6) Wu, S.; Lei, X.; Fan, E.; Sun, Z. Org. Lett. 2018, 20, 522. (7) Mampuys, P.; Zhu, Y.; Vlaar, T.; Ruijter, E.; Orru, R. V. A. B. U.; Maes, W. Angew. Chem., Int. Ed. 2014, 53, 12849. (8) (a) Nef, J. U.; Liebigs Ann. Chem. 1892, 270 (3), 267. (b) Livinghouse, T. Tetrahedron 1999, 55 (33), 9947. (9) (a) Mampuys, P.; Zhu, Y.; Sergeyev, S.; Ruijter, E.; Orru, R. V. A.; Van Doorslaer, S.; Maes, B. U. W. Org. Lett. 2016, 18, 2808−2811. (b) Bossio, R.; Marcaccini, S.; Pepino, R. Heterocycles 1986, 24 (7), 2003. (c) Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. Heterocycles 1996, 43 (2), 471. (10) (a) Siauciulis, M.; Sapmaz, S.; Pulis, A. P. D.; Procter, J. Chemical Science 2018, 9 (3), 754. (b) Jarboe, S. G.; Terrazas, M. S.; Beak, P. J. Org. Chem. 2008, 73 (24), 9627. (11) (a) McCune, C. D.; Beio, M. L.; Sturdivant, J. M.; de la SaludBea, R.; Darnell, B. M.; Berkowitz, D. B. J. Am. Chem. Soc. 2017, 139 (40), 14077. (b) Castell, J. V.; Tun-Kyi, A. Helv. Chim. Acta 1979, 62, 2507. (c) Samukov, V. V. Synth. Commun. 1998, 28 (17), 3213.
Scheme 4. Comparison of Synthetic Routes to Lesinurad 1
the drug lesinurad (compound 1 in Figure 1) can be synthesized in one step from the corresponding isocyanide using our three-component protocol in 52% isolated yield. Note that in this protocol NBS was used as the activator and was in excess so that direct bromination of the triazole at its 5position can occur after ring formation. In comparison, patent literature revealed several synthetic procedures of lesinurad with four or more steps from 2-amino-7-cyclopropylnaphthalene, and those procedures generally involve the formation and handling of the toxic [1,2,4]triazole-3-thiol intermediates (Scheme 4). The overall yield of our procedure is about 36%, well above the 4−21% range based on patent literatures. In summary, we developed a sulfenyl halide (and succinimide) based multicomponent protocol that involves Selectrophilic center and isocyanide through in situ activation of disulfides. The procedure is suitable to a wide range of nucleophiles for the formation of isothiourea or analogous moieties. Inparticular, when our procedure is employed in the synthesis of S-containing heterocycles, the advantages of mild reaction conditions, reduced purification steps, and ease of starting material accessibility will make our method a useful addition to existing methodologies.
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Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00275. General methods; experimental procedures and spectral data; 1H and 13C NMR spectra; and references (PDF) D
DOI: 10.1021/acs.orglett.9b00275 Org. Lett. XXXX, XXX, XXX−XXX
