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In recent years, significant advances in catalyst design by Blakey and Du Bois have led to the development of synthetically useful protocols for intramolecular enantioselective C-H amination of sulfamate esters. However, many challenges still remain in the synthesis of inexpensive and robust chiral catalysts capable of engaging a wide variety of nitrogen sources for regio- and stereocontrolled C-H amination. The Borovik group has developed a novel hydrooxazoline tripodal (H.O.T.) ligand which inspired us for the design of a new catalyst using inexpensive metal such as copper. We first screened different conditions for the synthesis of Cu(I)-H.O.T. catalyst (1). We also studied its catalytic activity for the C-H amination of sulfamate ester.
Catalytic intramolecular C-H amination has advanced as a general technology for chemical synthesis.1 DuBois and coworkers have revolutionized this area by developing protocol for both regio-2a,b and enantioselective2c efficient C-H amination using dimeric Rh(II) catalysts. The Blakey group has recently shown that new cationic Ru(II)-pybox catalysts were particularly effective for enantioselective C-H amination of benzylic and allylic sulfamate esters.3
Du Bois’ enantioselective C–H amination reaction
Blakey’s enantioselective C–H amination reaction
Although significant progress has been obtained in the design of chiral catalysts for C-H amination, the cost and the large number of steps of their preparation still remains a major drawback. We envisioned to develop a readily available and inexpensive novel catalyst using the H.O.T. ligand and Cu(I)Br as a metal source. Its synthesis and its catalytic ability for the C-H amination of sulfamate ester 2 have been studied.
Cu(I)-H.O.T. catalyst reaction
Inspired by our previous work with Ru(II)pybox-catalysts we postulated a potential catalytic cycle where cationic Cu(I)-complex could be the reactive species.
Proposed Cu(I)-H.O.T. catalytic cycle
Synthesis of Cu(I)-H.O.T. catalyst (1)
The H.O.T. ligand 4 was synthesized in two steps from inexpensive commercially available tris(2-aminoethyl)amine 3 according to the method developed by the Borovik Group4 with an overall yield of 89%.
The H.O.T. ligand 4 is then dissolved in an appropriate solvent with 1 equivalent of Cu(I)Br yielding Cu(I)-H.O.T. catalyst 1. 5
After screening several solvents, acetonitrile and toluene were selected as the most appropriate solvents for the metallation process.
Evaluation of catalytic activity on sulfamate ester (2)
Investigations6 performed using Cu(I)-H.O.T. catalyst 1
Representative HPLC trace (crude reaction mixture)
C-H amination using p-tosylcarbamate
Through our screenings of Cu(I)-H.O.T. catalyst 1 the complex’s susceptibility to oxidation became readily apparent. Therefore, we also studied the reaction of a pre-oxidized nitrogen source, p-tosylcarbamate, developed by Lebel and coworkers.7 After some first experiments, using 30 mol % of 1 and K2CO3 in acetonitrile, no C-H amination product 6 was observed.
The H.O.T. ligand is readily prepared in 2 steps starting from inexpensive commercially available materials. Different screenings of solvents have allowed us to synthesize complex 1. Recrystallizations are currently being performed in order to obtain an x-ray crystal structure of 1. First experiments using the new Cu(I)-H.O.T. catalyst 1 have shown promising results for the intramolecular C-H amination of sulfamate esters. Future experiments will involve different metals, solvents, and functionalization of the H.O.T. ligand by adding chirality.
SURE Program
Emory University Research Council
SIRE
HHMI No. 52005873
1. a) Davies, H. M. L., Manning, J. R. Nature 2008, 451, 417. b) Espino, C. G., Du Bois, J. In Modern Rhodium-Catalyzed Organic Reactions, Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005, 379.
2. a) Espino, C. G., Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598. b) Espino, C. G., When, P. M., Chow, J., Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935. c) Espino. C/ G,. Fiori, K. W., Kim, M., Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378. d) Zatalan, D. N., Du Bois, J. H. J. Am. Chem. Soc. 2008, 130, 9220. Liang, J.-L., Yuan, S.-X., Huang, J.-S., Che, C.-M. J. Org. Chem. 2004, 69, 3610.
3. Milczek, E., Boudet, N., Blakey, S. Angew. Chem. Int. Ed. 2008, 47, 6825.
4. Borovik Group. UC Irvine. 2009.
5. Procedure for the synthesis of cat. 1: In a glovebox, a 25 mL round bottom flask was charged with H.O.T. ligand 4 (0.071 mmol, 1 eq.). Acetonitrile (2 mL) or toluene (6 mL) was added followed by Cu(I)Br (0.071 mmol, 1 eq.). The resulting suspension was stirred for 2 hours at 23 oC or 18 hours at 23 oC, respectively. The catalyst was used without further purification. IR (liquid) 3354, 3273, 2877, 1719, 1672, 1252, 713 cm-1; HMRS (ESI) calc. for C15H27CuBrN7O3 [M]: 495.0655; found: 495.0644 (in THF).
6. Procedure for the synthesis of the oxathiazinane 5: In a glovebox a 25 mL round bottom flask was charged with 3-phenylpropyl sulfamate (0.23 mmol, 1 eq.), oxidant (0.26 mmol, 1.1 eq.), magnesium oxide (0.53 mmol, 2.3 eq.), and acetonitrile (1 mL) or toluene (5 mL). The resulting suspension was stirred for 10 minutes at 23 oC. In another flask the Cu(I)-H.O.T. catalyst was prepared in an appropriate solvent (acetonitrile or toluene) and silver triflate (0.071 mmol, 0.3 eq.) was added neat. The resulting suspension was stirred for 10 minutes at 23 oC then added to the reaction flask. The resulting suspension was stirred for 18 hours at 23 oC. The reaction was diluted with ethyl acetate (10 mL) and filtered over celite. The filter cake was washed with EtOAc. The filtrate was washed with 2x15 mL NH4OH and 2x15 mL brine. The organic layer was evaporated giving a crude mixture containing oxathiazinane 5 as an oil. The conversion ratio of the product was analyzed by a Chiracel OD-H column (UV detection at 210 nm).
7. Lebel, Helene. Chem. Eur. J. 2008, 14, 6222.
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