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UW-Madison CHEM 346 - CHEM 346 Lecture Notes

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J. Org. Chem. 1994,59, 1939-1942 1939 A Practical Method for the Large-Scale Preparation of EN,N-Bis(3,5-di- tert-but ylsalicy1idene)- 1,2-~yclohexanediaminato( 2-) ]manganese (111) Chloride, a Highly Enantioselective Epoxidation Catalyst Jay F. Larrow and Eric N. Jacobsen' Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138 Yun Gao,' Yaping Hong, Xiaoyi Nie, and Charles M. Zepp Sepracor Inc., 33 Locke Drive, Marlborough, Massachusetts 01 752 Received November 9, 1993 Introduction The use of catalytic asymmetric reactions for the synthesis of highly enantiomerically enriched chiral com- pounds is of growing importance in organic chemistry and in the chemical industry at large.' The practical utility of a catalytic asymmetric method is closely tied to the accessibility of the catalyst and can be severely undermined if the process for preparation of the catalyst proves too costly or technically-difficult for large-scale production. The chiral Mn(II1)-Schiff base complex 1 has recently emerged as the most enantioselective catalyst uncovered to date for the epoxidation of a wide variety of olefins.2 Herein we describe an efficient, highly-optimized proce- dure for the preparation of both enantiomers of 1 which is practical both on the laboratory scale and at the multihundred kilogram level.3 The ready accessibility of 1 is likely to facilitate its incorporation into a variety of laboratory and commercial applications. c) Results and Discussion The synthesis of catalyst 1 outlined in Schemes 1 and 2 involves three linear and four total steps from inexpensive precursors. Two key improvements have been effected over previously reported (sa1en)Mn catalyst ~yntheses.~d*~ (1) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. (b) Nugent, W. A.; RajanBabu, T. V.; Burk, M. J. Science 1993,259,479. (2) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. SOC. 1991,113,7063. (b) Lee, N. H.; Muci, A. R.; Jacobsen, E. N. Tetrahedron Lett. 1991,32,5055. (c) Lee, N. H.; Jacobsen, E. N. Tetrahedron Lett. 1991,32,6533. (d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992,57,4320. (e) Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993,58,6939. (f) Jacobsen,E. N.;Deng,L.;Furukawa,Y.;Martfnez, L. E. Tetrahedron, in press. (3) Catalyst 1 has been prepared in 75-100 kg batches at two toll- manufacturing facilities under contract from Sepracor, Inc. according to method B (see Experimental Section). (4) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. SOC. 1990,112,2801. (b) Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991,56, 2296. Scheme 1 A. n Ho OH HpOMOAc r-i w + )-ico,H - +H3N 0 NH3+ HpN NHp HOzC HOQH /\ -0pc cop- dl + meso B. 2 + 5e HZOlEtOH, 2 eq KpCO3 80°C c t-BuqOH HOGt-BU t-BU t-Bu 4 C. n 't-Bu &Bu' 1 Scheme 2 x x 30: X=CBu 3b: X&H3 3c: XIOCH:, 3d: XlCl 3e: XsBr The most important modification from the perspective of large-scale production is the application of the Duff reactions to the formylation of 2,4-di-tert-butylphenol(3a, Scheme 2). This procedure offers significant advantages over SnC4-mediated formylation2d*6 or the Reimer- Tiemann each of which involve toxic reagenta and require special handling. Although the Duff reaction is generally recognized as being low-yielding? the required salicylaldehyde derivative 5a was obtained in pure, crys- talline form in 40-50% yield under optimized reaction conditions. This yield was considered quite acceptable given that all of the reagents are very economical and easy to manipulate. The second significant improvement affecting the catalyst synthesis was tied to the resolution of 1,2- diaminocyclohexane.9 The monotartrate salt 2 was ob- tained in high diastereomeric purity from either the racemic trans-diamine or the commercial mixture of racemic trans- and cis-isomers. Precipitation from aque- ous acetic acid and application of a series of methanol (6) Duff, J. C.; Bills, E. J. J.Chem. SOC. 1934, 1305. (6) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J. Chem. SOC., Perkin Trans. 1 1980, 1862. (7) (a) Reimer, K. Ber. 1876,9,423. (b) Reimer, K.; Tiemann, F. Ber. 1876,9,824. (c) Reimer, K.; Tiemann, F. Ber. 1876,9,1268. (d) Reimer, K.; Tiemann, F. Ber. 1876, 9, 1285. (8) (a) Ferguson, L. N. Chem. Rev. 1946,38,227. (b) Fieser, M.; Fieaer, L. F. Reagents for Organic Synthesis; Wiley: New York, 1974; Vol. 4, p. 243. (9) Gasbel, F.; Steenbel, P.; Seremen, B. S. Acta Chem. Scad. 1972, 26, 3605. 0022-3263/94/1959-1939$04.50/0 0 1994 American Chemical Society1940 J. Org. Chem., Vol. 59, No. 7, 1994 Notes Representative Procedure for Formylation Reaction: 3,5- Di- tert-butyl-2-hydroxybenzaldehyde (ea). The procedure of Duff and Bills6 was followed with modifications. With mechanical stirring, 2,4-di-tert-butylphenol(l25 g, 0.61 mol, 1.0 equiv), hexamethylenetetramine (HMT, 170 g, 1.21 mol, 2.0 equiv), and glacial acetic acid (300 mL) were combined in a 2-L, three-necked, round-bottomed flask. The homogeneous mixture was heated to 130 "C over a period of 60 min or less and was maintained at this temperature (f5 "C) for 2 h. The mixture was cooled to 75 "C and 33 % (w/w) aqueous HzSOI (300 mL) was added. The stirred mixture was heated at reflux (105-110 "C) for 60 min before heating and stirring were discontinued. The mixture was allowed to cool to 75 "C and then transferred to a separatory funnel preheated to 75 "C with electrical heatingtape. The phasea were allowed to separate for 30 min at this temperature before the lower aqueous layer was removed. The organic layer was transferred to an Erlenmeyer flask and allowed to cool to 50 "C before methanol (100 mL) was added. The crude product crystallized from this mixture upon external cooling to 5 "C and was collected by vacuum filtration. Recrystallization from methanol12 (1:l w/v) afforded the desired compound as a free- flowing yellow solid (56-71 g, 40-50% yield) in 298% purity as determined by GC: mp 53-56 "C (lit.13 mp 58-60 OC); lH NMR 6 11.65 (a, 1 H), 9.87 (a, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 1.43 (a, 9 H), 1.33 (a, 9 H); l9C NMR 6 197.2, 159.2,141.7,137.8,131.9,127.8,120.2,35.1,34.3,31.4,29.4;HRMS (EI) mlz 234.1628 (calcd for M+ 234.1619). Anal. Calcd for 3-tert-Butyl-2-hydroxy-5-methylbenzahlehyde (5b). The modification of the Duff reaction


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