Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Dicyclopentyl Dithiosquarate as an Intermediate for the Synthesis of Thiosquaramides Michael Rombola and Viresh H. Rawal* Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States S Supporting Information *
ABSTRACT: A general and greatly improved route is reported for the synthesis of a variety of thiosquaramides from a common dithionated intermediate. Both diaryl thiosquaramides and bifunctional thiosquaramides are readily accessed from dicyclopentyl dithiosquarate via two addition− elimination reactions. The convenient handling characteristics and relative stability of associated intermediates enable an operationally simple thiosquaramide preparation. Bifunctional aryl thiosquaramides, which were inaccessible by the previous method, are also prepared, and their catalytic performance is demonstrated, including their capability to function as Brønsted acid catalysts.
S
ince the advent of hydrogen bond donor catalysis,1 two scaffolds have emerged as dominant platforms: thioureas2 and squaramides.3,4 The success of these compounds as catalysts can be attributed to the two-point hydrogen bond donor motif, which provides strong substrate activation and spatial orientation for asymmetric induction. The simple and routine nature of thiourea and squaramide preparations has contributed to their widespread adoption as catalysts: Thioureas are prepared in one step from an appropriate isothiocyanate and amine, and squaramides are prepared in two steps from dimethyl squarate and two amines (Scheme 1). Almost any amine can be used as a coupling partner, which allows the chemist to quickly build a library of compounds for screening in their reaction of interest.
preparation of even more acidic thiosquaramides, thereby enabling further advances in catalysis. Of particular interest were the hitherto unexplored bifunctional aryl thiosquaramides, which were expected to be among the most acidic members of the bifunctional squaramide family of catalysts. Among the challenges that one faces while developing a general route to these catalysts is the instability of many thiosquarate intermediates. The size of the alkyl group on the thiosquarate precursor affects its stability and its reactivity to amines. In prior studies, for example, we had found that the synthesis of dimethyl dithiosquarate presented difficulties, and the monodisplacement intermediates of other squarates were unstable to reaction conditions and standard purification methods. Through extensive studies, we have determined that certain bulkier secondary thioesters possess the needed reactivity and stability properties to serve as common intermediates to a wide range of thiosquaramides, including the sought-after bifunctional aryl thiosquaramides (Scheme 1). Several alkyl squarates were prepared and subjected to different thionation conditions, and illustrative results are summarized in Table 1. Thionation of n-butyl squarate 1a using Lawesson’s reagent gave the unstable, gelatinous dithiosquarate 2a. The reaction was stopped at partial conversion, since the product decomposed as the reaction progressed. Squarates of secondary alcohols gave better results. On reaction with 1 equiv of Lawesson’s reagent at room temperature in dichloromethane, 3-pentyl squarate 1b was converted to a near 1:1 mixture of the mono- and dithiosquarates (3a and 2b) after 14 h, and completely to the latter after 46 h (entries 2 and 3). Cyclopentyl squarate 1c was converted to the dithio-derivative
Scheme 1. General Synthesis of Squaramides and Thiosquaramides
We recently reported the first example of thiosquaramides as excellent hydrogen bond donors for asymmetric catalysis.5 While our method of catalyst preparation provided access to bifunctional alkyl thiosquaramides, it proved ineffective for making bifunctional aryl thiosquaramides, or aryl thiosquaramides more generally.6,7 The development of an improved and general synthesis of thiosquaramides, through a standardized and user-friendly procedure, was expected to allow the © XXXX American Chemical Society
Received: November 15, 2017
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DOI: 10.1021/acs.orglett.7b03549 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Thionation of Alkyl Squarates with Lawesson’s Reagent
entry
R
Lawesson’s reagent (equiv)
time (h)
1 2
n-butyl (1a) 3-pentyl (1b)
1.0 1.0
7 14
3 4
3-pentyl (1b) cyclopentyl (1c) cyclopentyl (1c)
1.0 1.0 0.5
5
X
Table 2. Addition of Amines to Cyclopentyl Dithiosquarate
yield (%) 14 30, 39
46 37
S (2a) S (2b), O (3a) S (2b) S (2c)
25
O (3b)
68
80 71
(2c) in good yield; workup of the reaction followed by silica gel chromatography afforded the pure dithione as a fluffy orange solid. The use of 0.5 equiv of Lawesson’s reagent gave the monothionation product (3b) in good yield. Of the different dithiosquarates examined, dithiosquarate 2c has been found to be the preferred intermediate for making thiosquaramides because of its superior handling characteristics and reactivity, especially with less reactive amines, such as electron-deficient anilines. Whereas dithiosquarate 2b is a red oil that continues to darken, 2c is a stable solid: a sample left under ambient conditions displayed no noticeable decomposition after 1 week. Cyclopentyl dithiosquarate (2c) provided an excellent platform for the synthesis of various di- and monodisplacement squaramide derivatives (Table 2). Primary and secondary amines reacted vigorously with 2c. Indeed, if no cooling was employed or the addition of the amine was too rapid, the reactions with benzylamine or cyclohexylamine to produce 4a or 4b were sufficiently exothermic as to cause the solvent to boil. Sterically bulky amines were less reactive. Addition of tertbutyl amine produced the desired thiosquaramide 4c in only 30% yield after 2 h. Longer reaction times did not improve yield (36% yield after 42 h), and using an excess of the amine led to byproduct formation. Treatment of 2c with an excess of the appropriate aniline led to diaryl thiosquaramides.8 Even the electron-deficient 3,5-(bistrifluoromethyl)aniline was a suitable reaction partner, producing the diaryl thiosquaramide 4f in the absence of a catalyst.9 The bulkiness of the amine heavily influenced its rotameric composition. NMR experiments revealed compound 4c existed as a single rotamer in DMSO at room temperature, while compound 4a existed as three rotamers in a ratio of 26:9:2. Compound 4b is present predominantly as one rotamer. Despite the high reactivity of 2c toward addition− elimination reactions, monodisplacement products can still be prepared by using less than 1 equiv of the amine (entries 7− 12). The slightly lower isolated yield of cyclopentyl dithiosquarate 5c than 3-pentyl dithiosquarate 5d belies the greater reactivity of 2c over 2b. The lower yield of 5b is due to competitive diaryl thiosquaramide formation, indicating that the monoaddition product is quite reactive to a second addition−elimination reaction. When coupled with a chiral diamine, the monodisplacement products provide access to various bifunctional thiosquaramide catalysts (Scheme 2). Thus, monobenzylamino dithiosquarate 5a was converted in 90% yield to 6a, a catalyst that was used for
a
Compound 2b was used instead of 2c.
enantioselective barbituric acid additions to nitroalkenes.5 Importantly, the present route to 6a is not only more robust, but, unlike the earlier route, it also opens access to bifunctional thiosquaramides possessing various anilines. Some bifunctional thiosquaramides are sensitive to silica gel chromatography. Catalysts 6b, 6c, and 6e and were isolated by silica gel chromatography, whereas 6a, 6d, 6f, and 6g were isolated by trituration. Bifunctional thiosquaramides, especially those possessing an aryl substituent, display complex NMR spectra, presumably due to the presence of zwitterionic species and restricted rotation (Scheme 3). We have found that protonation of these compounds with HCl simplifies their spectra and sharpens many signals. B
DOI: 10.1021/acs.orglett.7b03549 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Bifunctional Thiosquaramide Synthesis
Scheme 5. Evaluation of Oxo- and Thiosquaramide Catalyst Performancea
a
Conversion determined by 1H NMR spectroscopy.
higher than that obtained using our recently reported bifunctional alkyl thiosquaramide 6a. These initial studies demonstrate the superior capability of this new class of bifunctional catalysts. Furthermore, the higher acidity expected of aryl thiosquaramides5,7a opens up the possibility of their functioning as Brønsted acids.11 To probe this capability, we examined the aza-Diels−Alder reaction between 2-siloxydiene 13 and Nbenzylideneaniline 14, which has been reported to be catalyzed by bis(trifluoromethane)sulfonimide (Tf2 NH) to afford tetrahydropyridine 14 in up to 85% yield and 4:1 dr (Scheme 6).12,13 Remarkably, the reaction catalyzed by thiosquaramide
Scheme 3. Protonation of Bifunctional Thiosquaramides for NMR Characterization
Scheme 6. Aza-Diels−Alder Reaction Using a Thiosquaramide as a Brønsted Acid Catalysta
The described methodology also allows the synthesis of bifunctional monothiosquaramides with complete regiocontrol (Scheme 4). The reaction of tert-butylaminomonothiosquarate 7, obtained upon selective displacement of the alkoxy in conjugation with the thiocarbonyl group, with the requisite chiral diamine yielded bifunctional monothiosquaramide 8. Compound 8, like its dithio-congener, is more soluble in CH2Cl2 than the corresponding dioxosquaramide. Conversion of even one of the carbonyl groups to a thiocarbonyl disfavors the formation of hydrogen bonded ladder networks of oxosquaramides. This new class of squaramides promises to open up further opportunities in catalysis.
a
Yield determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
Scheme 4. Bifunctional Monothiosquaramide Synthesis 4f afforded DA-adduct 15 in 77% yield with a 2.7:1 dr (major diastereomer shown). Neither the oxosquaramide of 4f nor Schreiner’s thiourea catalyzed the reaction, yielding only recovered starting material.14 We are currently developing chiral aryl thiosquaramides for the catalysis of asymmetric reactions. In summary, we have developed a unified route to thiosquaramides. Bifunctional aryl thiosquaramides have been made for the first time, and their catalytic performance has been demonstrated, as has the potential for their use as Brønsted acid catalysts. The ready access to this new class of catalysts is expected to further expand the reaction space in hydrogen bonding catalysis.
Since bifunctional aryl thiosquaramides have not been previously reported, we have carried out preliminary studies to calibrate their performance against their oxosquaramide counterparts in the known conjugate addition reaction of lawsone (9) to β,γ-unsaturated α-keto ester 10 (Scheme 5).10 All thiosquaramides tested gave higher enantioselectivities than their corresponding oxosquaramides. Moreover, even without any optimization, bifunctional aryl thiosquaramide 6d gave the conjugate addition product in 94% ee, which is considerably C
DOI: 10.1021/acs.orglett.7b03549 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(9) The spectroscopic data for 4f are consistent with those of 4d and 4e, but differed from that reported in the literature. Cf. ref 7a. (10) (a) Chen, X.; Zheng, C.; Zhao, S.; Chai, Z.; Yang, Y.; Zhao, G.; Cao, W. Adv. Synth. Catal. 2010, 352, 1648. (b) Wang, Y.; Zhang, W.; Luo, S.; Zhang, G.; Xia, A.; Xu, X.; Xu, D. Eur. J. Org. Chem. 2010, 2010, 4981. (c) Gao, Y.; Ren, Q.; Ang, S.; Wang, J. Org. Biomol. Chem. 2011, 9, 3691. (d) Lee, J. H.; Kim, D. Y. Bull. Korean Chem. Soc. 2013, 34, 1619. (11) Recent reviews: (a) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277. (b) Min, C.; Seidel, D. Chem. Soc. Rev. 2017, 46, 5889. (12) Takasu, K.; Shindoh, N.; Tokuyama, H.; Ihara, M. Tetrahedron 2006, 62, 11900. (13) For examples of Brønsted acid catalyzed enantioselective azaDiels−Alder reactions, see: (a) Rueping, M.; Raja, S. Beilstein J. Org. Chem. 2012, 8, 1819. (b) Beceño, C.; Krappitz, T.; Raabe, G.; Enders, D. Synthesis 2015, 47, 3813. (c) Hatanaka, Y.; Nantaku, S.; Nishimura, Y.; Otsuka, T.; Sekikaw, T. Chem. Commun. 2017, 53, 8996. (d) Review: Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. Diels-Alder Reactions of Imino Dienophiles. In Organic Reactions; Overmann, L. E., Ed.; Wiley: 2005; Vol. 65, Chapter 2. (14) Since oxosquaramide (12e) is poorly soluble in PhMe, the reaction was also performed in CH2Cl2, but gave no product.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03549. Experimental procedures and detailed characterization data of all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Michael Rombola: 0000-0002-4402-5619 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Science Foundation (NSF-1566402) for financial support of this work.
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REFERENCES
(1) For selected pioneering examples of enantioselective hydrogen bond donor catalysis, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (c) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146. (d) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. (2) For early examples of thiourea based bifunctional catalysis, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (b) Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466. (3) For pioneering applications of squaramides as asymmetric organocatalysts, see: (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. (b) Lee, J. W.; Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Jang, H. B.; Song, C. E. Chem. Commun. 2009, 7224. (c) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153. (d) For a recent review on squaramide-catalyzed reactions, see: Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. (4) Further along the continuum of strong hydrogen bond donors are phosphoric acids, which have played a major role in catalysis. For a recent review, see: Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (5) Rombola, M.; Sumaria, C. S.; Montgomery, T. D.; Rawal, V. H. J. Am. Chem. Soc. 2017, 139, 5297. (6) (a) Seitz, G.; Morck, H.; Mann, K.; Schmiedel, R. Chem.-Ztg. 1974, 98, 459. (b) Eggerding, D.; West, R. J. Org. Chem. 1976, 41, 3904. (c) Ehrhardt, H.; Hünig, S.; Pütter, H. Chem. Ber. 1977, 110, 2506. (d) Frauenhoff, G. R.; Takusagawa, F.; Busch, D. H. Inorg. Chem. 1992, 31, 4002. (e) Müller, M.; Heileman, M. J.; Moore, H. W.; Schaumann, E.; Adiwidjaja, G. Synthesis 1997, 1997, 50. (7) Diaryl thiosquaramides have been reported, but the methodology was not amenable to synthesizing the bifunctional thiosquaramides. See: (a) Busschaert, N.; Elmes, R. B. P.; Czech, D. D.; Wu, X.; Kirby, I. L.; Peck, E. M.; Hendzel, K. D.; Shaw, S. K.; Chan, B.; Smith, B. D.; Jolliffe, K. A.; Gale, P. A. Chem. Sci. 2014, 5, 3617. (b) Elmes, R. B. P.; Busschaert, N.; Czech, D. D.; Gale, P. A.; Jolliffe, K. A. Chem. Commun. 2015, 51, 10107. (8) Dithiosquarate 2c is considerably more reactive to nucleophiles than its oxo-analog. The analogous reaction to produce diaryloxosquaramide is performed at 100 °C with zinc triflate as catalyst. See: Rostami, A.; Colin, A.; Li, X. Y.; Chudzinski, M. G.; Lough, A. J.; Taylor, M. S. J. Org. Chem. 2010, 75, 3983. D
DOI: 10.1021/acs.orglett.7b03549 Org. Lett. XXXX, XXX, XXX−XXX
