The first synthesis of an enantiomerically pure C2 symmetric benzothiadiazole 2-oxide is described along with the first synthesis of an enantiomerically thiadiazol-3-one 1-oxide and a thiatriaza-indene 3-oxide system both chiral at the sulfur atom. Excellent levels of diastereoselectivity were observed in the SO installation step, that is, the reaction of the prerequisite bis-amines with thionyl chloride at ambient temperature

Benjamin Buckley (1249668)

Mark Elsegood (1249893)

Stephen P. Neary (7162853)

Tetrahedron Asymmetry

English

Loughborough University Institutional Repository

   This item was submitted to Loughborough’s Institutional Repository (https://dspace.lboro.ac.uk/) by the author and is made available under the following Creative Commons Licence conditions.      For the full text of this licence, please go to: http://creativecommons.org/licenses/by-nc-nd/2.5/   Tetrahedron: Asymmetry  1 The First Enantiomerically Pure Thiadiazol-3-one 1-oxide and Thiatriaza-indene 3-Oxide Systems Chiral at the Sulfur atom Benjamin R. Buckley,* Stephen P. Neary and Mark R. J. Elsegood Department of Chemistry. Loughborough University, Ashby Road, Loughborough, Leicestershire, LE11 3TU, UK  Abstract— The first synthesis of an enantiomerically pure C2 symmetric benzothiadiazole 2-oxide is described along with the first synthesis of a enantiomerically thiadiazol-3-one 1-oxide and a thiatriaza-indene 3-Oxide system both chiral at the Sulfur atom. Excellent levels of diasteroselectivity were observed in the SO installation step, i.e. reaction of the prerequisite bis-amines with thionyl chloride at ambient temperature. © 2014 Elsevier Science. All rights reserved 1.0 Introduction There are a wide number of reports utilizing a 1,3-dinitrogen skeleton as a basis for catalyst/ligand design; for example, N-heterocyclic carbenes 1,1 phosphoramides 2,2 and thioureas 3 (Figure 1).3 Indeed 1,3-amines and imines have themselves been reported as ligands and catalysts. However, there are very few reports regarding the synthesis of structurally related thiadiazolidines 4 or thiadiazolidine oxides 5. The majority of reports regarding thiadiazolidine-1,1-dioxides 6 relate to their pharmacological properties,4 the zwitterion 7 has been used in a Mitsunobu-type reaction5 and 8 has been employed as a chiral auxiliary in reactions which have traditionally used the Oppolzer sultam.6 Thiadiazolidine 1,1-dioxides have also been reported as useful polar aprotic solvents7 and as key intermediates for the synthesis of constrained peptides.8 We were particularly attracted to the thiadiazolidine oxides as we postulated that they may be interesting and useful ligands for phosphine free metal-catalysed reactions. NSNO OPPhPhPh HN SNHPh PhO ONSNR R N SNR R N SNR RO O ON NNNPONN NS1 2 34 5 6 7 8  Figure 1. Various 1,3-dintrogen containing compounds To this end we were the first to report the highly active thiadiazolidine 1-oxide 9 catalyst system in the Mizoroki–Heck reaction (Scheme 1).9 Excellent yields of stilbenes derived from aryl iodides and bromides have been achieved using as little as 0.00002 mol% catalyst. The ligand/palladium system can be stored as a stock solution open to air at room temperature with no observable loss of activity for a period of several months.  R1RR X RNSNO (0.0008 mol%)Pd(dba)2 (0.0001 mol%), NMP, NaOAc, TBABX = I, Br up to 99% yield9 Scheme 1. Application of the thiadiazolidine 1-oxide system for the Mizoroki-Heck reaction. The synthesis of the mesityl-derived thiadiazolidine 1-oxide ligand 9 was easily achieved in two steps; mesityl amine and glyoxal were reacted neat, and upon formation of the bright yellow bis-imine, sodium borohydride/ethanol was added to furnish the bis-amine 10 in excellent yield (Scheme 2). Treatment of a solution of 10 in diethylether/triethylamine with thionyl chloride afforded the thiadiazolidine oxide 9 in good yield. NSNONH2 i) Glyoxal, neat 10 minii) NaBH4, EtOH,12 h, 93%NH HNThionyl ChlorideEt3N, Et2O, 0ºC12 h 83%109  Scheme 2. Synthesis of the thiadiazolidine 1-oxide 9 Our strategy for the development of highly enantioselective catalysis revolves around the fact that if the substituents attached at the nitrogen atoms of a thiadiazolidine 1-oxide system are non-equivalent then the sulfur atom will be chiral. This means that the controlling chiral element for  Pergamon TETRAHEDRON: ASYMMETRY  Tetrahedron: Asymmetry 2 asymmetric catalysis will be directly attached to the metal atom and hence will be closer to the site of the reaction. This should then impart high levels of enantiomeric excess. The corresponding phosphine systems have been shown to impart high levels of enantiomeric excess, prominent examples of chiral phosphorus ligand systems are the C2-symmetric non-functionalized bisphospholane ligands DuPHOS, and BPE and the oxyfunctionalized bisphospholanes RoPHOS and BASPHOS, as well as several monophospholanes being part of mono- or bidentate ligands. However, the discovery of new, efficient P-chiral bisphosphanes has been slow, partly because of the difficulties in ligand synthesis, and their synthetic routes are characterized by several disadvantages, e.g. poor air stability, low variability, limited tolerance of functional groups and serious problems during up scaling due to extreme or hazardous reaction conditions. Hence, we believe our systems will add significant value to this highly topical area. To the best of our knowledge, the synthesis and application of the enantiomerically pure C2 symmetric benzothiadiazoline 1-oxide, and the thiadiazol-3-one 1-oxide and thiatriazoline 1-oxide systems chiral at sulfur have not been reported. This communication details our efforts to synthesize the first such examples. 2.0 Results and Discussion For simplicity we initially chose to prepare a C2 symmetric ligand. Diver has reported the use of C2 symmetric carbenes based on a benzimidazole structure,10 and this prompts us to describe our own results in this area. Such a design of ligand is attractive because both of the enantiomers are, in principle, available, and because the ligands can be readily accessed through a short synthetic sequence; for example, the 1,2-bis-α-methylbenzylaniline 11 was easily prepared as shown in Scheme 3. The use of two sequential Buchwald-Hartwig couplings nevertheless proved frustrating as the second reaction consistently gave a lower yield than expected: reaction of the amine with BrBrBrNHPhMeNHNHPhMePhMePhCH(Me)NH2BINAP, NaOtButoluene, 110°C 87%PhCH(Me)NH2BINAP, NaOtButoluene, 110°C60%11 Scheme 3. Synthesis of the 1,2-bis-α-methylbenzylaniline 11.11 1,2-dibromobenzene gave the monosubstituted product in an excellent 87% yield, but attempts to introduce the second amine gave the desired product in no more than a respectable 60% yield in our hands. Treatment of 1,2-bis-α-methylbenzylaniline 11 with thionyl chloride in diethylether/triethylamine afforded the C2 symmetric benzothiadiazole 2-oxide 12 in a disappointing 30% yield (Scheme 4). NHNHPhMePhMe11SOCl2, Et3N,Et2O, 0ºC - r.t.18 h NSNOMe PhMe Ph12  Scheme 4. Synthesis of the benzothiadiazole 2-oxide 12. 11 We have also attempted the synthesis of a related C2 symmetric system outlined in Scheme 5.12 Unfortunately cyclization to incorporate the SO moiety proved unsuccessful perhaps due to the steric crowding of the two nitrogen atoms. SOCl2, Et3N,Et2O, 0ºC - r.t.18 hNH2NH2BINAP, NaOtButoluene, 110°C 75%BrNHNHNNS OX Scheme 5. Attempted synthesis of a cyclohexyldiamine derivative. 11 In order to develop a synthesis of a system chiral at sulfur we chose to prepare a thiatriazoline 1-oxide as the synthesis of enantiomerically pure unsymmetrical 1,3-diamines has been reported to be non-trivial.13 Leeper,14 Enders,15 Rovis16 and others17 have shown that the NHC triazolium systems are capable of delivering high enantioselectivities in a variety of transformations, hence we chose a similar route to prepare the thiatriaza-indene 3-oxide 13. Thiatriaza-indene 3-oxide 13 was synthesized using the following protocol (Scheme 6): coupling of ethylchloroacetate and phenylglycinol under basic conditions afforded the amide 14 in 61% yield. The amide moiety was then converted to the imino ether 15 using trimethyloxonium tetraflouroborate Addition of HO NH2PhEthylchloroacetateNaH, THF, ∆18 h NHOOPh NOOMePhi) Me3O+BF4–CH2Cl2, r.t., 18 hii) aq. NaHCO361% 15 42%PhenylhydrazinehydrochlorideMeOH, ∆3 hNHONPhHN PhSOCl2, Et3N (3 eq.)0ºC - r.t.18 hNOPhS NNO Ph16 30% 71%1314.HCl Scheme 6. Synthesis of the thiatriaza-indene 3-oxide 13. 11     Figure 2. X-ray crystal structure of 13.  Tetrahedron: Asymmetry  3phenylhydrazine hydrochloride afforded the a bis-amine precursor 16 which was suitable for treatment with thionyl chloride under the standard conditions to afford the intended target molecule 13 as a single diastereoisomer (as determined by 1H and 13C NMR spectroscopy) in 71% yield. Compound 13 was found to be crystalline and the X-ray crystal structure18 is shown in Figure 2. It is interesting to note that the oxygen at sulfur is on the opposite face to that of the phenyl group in the morpholine ring system. We next turned our attention to preparing a thiadiazol-3-one 1-oxide and this was achieved initially by the esterification of phenylalanine 17, followed by conversion of the ester moiety to the secondary amide 18 using methylamine. The primary amine was then protected with a p-methoxybenzyl group and subsequent treatment of the bis-amine 19 with thionyl chloride resulted in the final product 20 in four simple steps (Scheme 6). Unfortunately compound 20 was an oil and we have as yet been unsuccessful in determining the absolute stereochemistry at sulfur. By 1H and 13C NMR spectroscopy compound 20 appears to be a single diastereoisomer. SOCl2, CH2Cl20ºC - r.t.18 hOHONH2PhAcCl, MeOH,∆, 2 hOMeONH2Ph.HCli) R-NH2, EtOHii)NaHCO3 (sat. aq.)NHONH2Ph Ri) 4-MeOC6H4CHOMeOHii) NaBH4NHONHPh RPMBNONPh RPMB SO99% 62% 19 54% 20  48%1718  Scheme 7. Synthesis of the thiadiazol-3-one 1-oxide 20. 11  3.0 Conclusion We have successfully synthesized the first example of a enantiomerically pure C2 symmetric benzothiadiazole 2-oxide. We have also prepared the first thiatriaza-indene 3-oxide and thiadiazol-3-one 1-oxide systems chiral at the sulfur atom in high diastereoselectivity. We shall now endeavor to apply these and related systems in asymmetric catalysis. Acknowledgments The authors would like to thank Loughborough University for funding a PhD studentship (SPN) and Research Councils UK for a RCUK fellowship (BRB). References 1 (a) Arduengo, A. J. Acc. Chem. Res. 1999, 32, 913; (b) Herrmann, W. A.; Goossen, L. J.: Köcher, C.; Artus, G. R. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2805; (c) Herrmann, W. A.; Goossen, L. J.; Artus, G. R. J.; Köcher, C. Organometallics 1997, 16, 2472; (d) Seiders, J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225; (e) Perry, M. C.; Burgess, K. Tetrahedron:Asymmetry 2003, 14, 951; (f) Page, P. C. B.; Buckley, B. R.; Christie, S. D. R.; Edgar, M.; Poulton, A. M.; Elsegood, M. R. J.; McKee, V. J. Organomet. Chem. 2005, 690, 6210; (g) Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1290; (h) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619; (i) Kühl, O. Chem. Soc. Rev. 2007, 36 592; (j) Liddle, S. T.; Edworthy, I. S.; Arnold, P. L. Chem. Soc. Rev. 2007, 36, 1732; (k) Hahn, F. E.; Jahnke, M. C. Angew. Chem. Int. Ed. 2008, 47, 3122; (l) Arnold, O. L.; Casely, I. J. Chem. Rev., 2009, 109, 3599; (m) Lin, J. C. Y.; Huang, R. T. W.; Lee, C. S.; Bhattacharyya, A.; Hwang, W. S.; Lin, I. J. B. Chem. Rev., 2009, 109, 3561; (n) Vougioukalakis, G. C; Grubbs R. H. Chem. Rev., 2010, 110, 1746. 2 Denmark, S. E.; Heemstra, J. R. J. Org. Chem. 2007, 72, 5668 and references cited therein. 3 Yang, D.; Chen, Y.-C.; Zhu, N.-Y. Org. Lett. 2004, 6, 1577.  4 (a) Hultén, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon, B.; Danielson, U. H.; Karlén, A.; Kvarnström, I.; Samuelsson, B.; Hallberg, A. J. Med. Chem. 1997, 40, 885; (b) Bäckbro, K.; Löwgren, S.; Österlund, K.; Atepo, J.; Unge, T.; Hultén, J.; Bonham, N. M.; Schaal, W.; Karlén, A.; Hallberg, A. J. Med. Chem. 1997, 40, 898. 5 Castro, J. L.; Matassa, V. G.; Ball, R. G. J. Org. Chem. 1994, 59, 2289. 6 (a) Ahn, K.-H.; Yoo, D.-J.; Kim, J.-S. Tetrahedron Lett. 1992, 33, 6661; (b) Pansare, S. V.; Rai, A. N.; Kate, S. N. Synlett 1998, 623; (c) Sartor, D.; Saffrich, J.; Helmchen, G.; Richards, C. J.; Lambert, H. Tetrahedron: Asymmetry 1991, 2, 639; (d) Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernadinelli, G. Tetrahedron Lett. 1991, 32, 61; (e) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. Tetrahedron Lett. 1991, 32, 4893. 7 Richey, Jr., H.G.; Farkas Jr., J. J. Org. Chem. 1987, 52, 479. 8 (a) Dewynter, G.; Ubaldi, S.; Voyer, N.; Toupet, L. Tetrahedron Lett. 1998, 39, 7434; (b) Boudjabi, S.; Dewynter, G.; Voyer, N.; Toupet, L. Eur. J. Org. Chem. 1999, 9, 2275; (c) Regainia, Z.; Abdaoui, M.; Aouf, N. E.; Dewynter, G.; Montero, J. L. Tetrahedron 2000, 56, 381.  9 Buckley, B. R.; Neary, S. P. Adv. Synth. Catal. 2009, 351, 71. 10 Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673. 11 All novel compounds were characterized by melting point, optical rotation, infra red, combustion analysis, 1H & 13C NMR spectroscopy, mass spectrometry, and accurate mass analysis. 12 For the synthesis and use of related C2 symmetric carbene ligands/catalysts see for example: (a) Duguet, N.; Campbell, C. D.; Slawin A. M. Z.; Smith, A. D. Org. Biomol. Chem., 2008, 6, 1108; (b) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett., 2001, 3, 3225; (c) Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc., 2007, 129, 9568.  Tetrahedron: Asymmetry 4 13 Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008, 10, 957. 14 Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin 1 1998, 1891. 15 (a) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta. 1996, 79, 1899. (b) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743. 16 (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725. 17 See for related C2 symmetric N-heterocyclic carbene examples: (a) Cardinal-David, B.; Raup, D. E. A. Scheidt, K. A. J. Am. Chem. Soc., 2010, 132, 5345 and references cited therein; (b) Li, G.-Q.; Dai, L.-X. You, S.-L. Org. Lett., 2009, 11, 1623; (c) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P. L.; Ye, S. Org. Lett., 2008, 10, 277; (d) Concellón, C.; Duguet, N; Smith, A. D. Adv. Synth. Catal., 2009, 351, 3001 and references cited therein. 18 Crystal data for enantiopure 13: C16H15N3O2S, M = 313.37, monoclinic, P21, a = 7.3744(4), b = 8.8835(5), c = 12.0593(7) Å, β = 105.7428(8)°, V = 760.38(7) Å3, Z = 2, Dc = 1.369 g cm-3, µ(Mo-Kα) = 0.223 mm-1, T = 150(2) K, colourless plate, 1.05×0.61×0.06 mm3; 8881 reflections measured as above; 4509 independent, data corrected as above (min. and max. transmission factors: 0.800, 0.987), Rint = 0.0168, structure solved by direct methods, F2 refinement, R1= 0.0323 for 4266 data with F2> 2σ(F2), wR2 = 0.0826 for all data; 199 parameters; absolute structure parameter  x = –0.01(5). CCDC 783758 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 

The first enantiomerically pure thiadiazol-3-one 1-oxide and thiatriaza-indene 3-oxide systems chiral at the sulfur atom

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The first enantiomerically pure thiadiazol-3-one 1-oxide and thiatriaza-indene 3-oxide systems chiral at the sulfur atom

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