Stereoselective Aminooxygenation
(s, 3 H), 1.08 (s, 3 H), 1.00 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.1, 139.6, 136.7, 128.5, 128.3, 126.6, 126.1, 121.7,
78.8, 63.4, 59.8, 47.8, 43.4, 39.5, 39.1, 35.1, 33.1, 33.0, 31.3, 29.1,
served in reactions with the meso substrate 1a (e.g. Table 1,
Entry 1). Transition state C (substrate 7c) may be more
favorable than transition state A (substrate 1a) since the α-
substituent in TS A is in an axial position. We are currently
investigating this further with molecular modeling calcula-
tions.
20.3, 20.1, 17.0 ppm. IR (neat, thin film): ν = 2965, 2870, 1599,
˜
1475, 1348, 1160, 1137, 1116, 1049, 757, 701 cm–1. HRMS (ESI)
calcd. for C35H55O3N2S [M + H]+ 583.3928; found 583.3941.
Minor Pyrrolidine (؎)-cis-6e was obtained as a clear, colorless oil:
1H NMR (500 MHz): δ = 1.95 (m, 1 H), 1.82 (m, 1 H), 1.64 (m, 1
H), 1.46–1.49 (m, 6 H), 1.35 (s, 18 H), 1.33 (s, 3 H), 1.26 (s, 3 H),
1.16 (s, 3 H), 1.11 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
151.9, 140.5, 137.0, 128.4, 128.3, 126.5, 126.0, 121.4, 77.8, 62.0,
60.1, 59.6, 47.5, 43.7, 39.8, 35.5, 35.0, 33.4, 32.8, 31.2, 30.3, 20.4,
Experimental Section
Representative Procedures for Catalytic Diastereoselective Amino-
oxygenation of Alkenes
17.0 ppm. IR (neat, thin film): ν = 2964, 2366, 1599, 1454, 1348,
˜
1-{[(2S,5S)-5-Methyl-1-tosylpyrrolidin-2-yl]methoxy}-2,2,6,6-tetra-
methylpiperidine (2c): Table 2, Entry 2. Sulfonamide 1c (40 mg,
0.158 mmol, 1 equiv.), Cu(EH)2 (11 mg, 0.032 mmol, 0.2 equiv.),
TEMPO (74 mg, 0.474 mmol, 3 equiv.), K2 CO3 (22 mg,
0.158 mmol, 1 equiv.) and xylenes (1.6 mL) were combined in a
100 mL round-bottom flask equipped with a magnetic stir bar. The
flask was fitted with a glass side-arm adapter tapered to connect
to a short rubber vacuum hose, through which O2 (balloon) was
introduced. The reaction mixture was heated to 120 °C and stirred
for 24 h. The cooled solution was filtered through an SiO2 plug,
with Et2O washing. Concentration in vacuo and flash chromatog-
raphy on SiO2 (5% EtOAc in hexanes) afforded disubstituted pyr-
rolidine 2c (61 mg, 94%) as a white solid. The diastereoselectivity
1246, 1166, 1030, 751, 701 cm–1. HRMS (ESI) calcd. for [M +
H]+ C35H55O3N2S: 583.3928; found 583.3938.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details and spectroscopic data for all
new compounds.
Acknowledgments
We gratefully acknowledge the National Institutes of Health,
NIGMS (GM078383) for financial support of this project.
1
[1] Representative recent metal-catalyzed intramolecular carbo-
aminations: Cu-catalyzed: a) L. Miao, I. Haque, M. R. Man-
zoni, W. S. Tham, S. R. Chemler, Org. Lett. 2010, 12, 4739–
4741; b) W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007, 129,
12948–12949; Pd-catalyzed: c) D. N. Mai, J. P. Wolfe, J. Am.
Chem. Soc. 2010, 132, 12157–12159; d) W. He, K. T. Yip, N. Y.
Zhu, D. Yang, Org. Lett. 2009, 11, 5626–5628; Au-catalyzed:
e) G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc.
2010, 132, 1474–1475; f) W. E. Brenzovich Jr., D. Benitez, A. D.
Lackner, H. P. Shunatona, E. Tkatchouk, W. A. Goddard III,
F. D. Toste, Angew. Chem. Int. Ed. 2010, 49, 5519–5522; g) T.
de Haro, C. Nevado, Angew. Chem. Int. Ed. 2011, 50, 906–910.
[2] Representative metal-catalyzed intramolecular alkene diamin-
ations: Cu-catalyzed: a) F. C. Sequeira, B. W. Turnpenny, S. R.
Chemler, Angew. Chem. Int. Ed. 2010, 49, 6365–6368; Pd-cata-
lyzed: b) J. Streuff, C. H. Hovelmann, M. Nieger, K. Muniz, J.
Am. Chem. Soc. 2005, 127, 14586–14587; c) P. A. Sibbald, F. E.
Michael, Org. Lett. 2009, 11, 1147–1149; Ni-catalyzed d) K.
Muniz, J. Streuff, C. H. Hoevelmann, A. Nunez, Angew. Chem.
2007, 119, 7255; Angew. Chem. Int. Ed. 2007, 46, 7125–7127;
Au-catalyzed: e) A. Iglesias, K. Muniz, Chem. Eur. J. 2009, 15,
10563–10569.
[3] Representative metal-catalyzed intramolecular aminooxygen-
ations: Cu-catalyzed: a) P. H. Fuller, J. W. Kim, S. R. Chemler,
J. Am. Chem. Soc. 2008, 130, 17638–17639; b) E. S. Sherman,
S. R. Chemler, Adv. Synth. Catal. 2009, 351, 467–471; c) D. E.
Mancheno, A. R. Thornton, A. H. Stoll, A. D. Kong, S. B.
Blakey, Org. Lett. 2010, 12, 4110–4113; Pd-catalyzed: d) E. J.
Alexanian, C. Lee, E. J. Sorensen, J. Am. Chem. Soc. 2005, 127,
7690–7691; e) L. V. Desai, M. S. Sanford, Angew. Chem. 2007,
119, 5839; Angew. Chem. Int. Ed. 2007, 46, 5737–5740; f) P.
Szolcsanyi, T. Gracza, Chem. Commun. 2005, 3948–3950; g)
D. V. Liskin, P. A. Sibbald, C. F. Rosewall, F. E. Michael, J.
Org. Chem. 2010, 75, 6294–6296; Os-catalyzed: h) T. J. Don-
ahoe, G. H. Churchill, K. M. P. Wheelhouse, P. A. Glossop,
Angew. Chem. 2006, 118, 8193; Angew. Chem. Int. Ed. 2006,
45, 8025–8028.
(Ͼ 20:1) was determined from the crude H NMR spectrum. The
cis stereochemistry of 2c was assigned by NOE experiments. Data
for cis-2c: M.p. 121–125 °C. [α]2D0 = –63.9° (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.29 (d,
J = 8.0 Hz, 2 H), 3.90 (dd, J = 9.0, 3.5 Hz, 1 H), 3.84 (t, J = 8.0 Hz,
1 H), 3.72 (m, 1 H), 3.62 (m, 1 H), 2.41 (s, 3 H), 1.91 (m, 1 H),
1.67–1.55 (m, 3 H), 1.50–1.43 (m, 6 H), 1.36 (d, J = 6.0 Hz, 3 H),
1.18 (s, 3 H), 1.16 (s, 3 H), 1.09 (s, 3 H), 1.08 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 143.1, 135.0, 129.5, 127.6, 78.6, 60.0,
57.4, 39.6, 32.9, 32.5, 27.3, 22.8, 21.4, 20.2, 17.0 ppm. IR (neat,
thin film): ν = 2976, 2931, 2877, 1591, 1460, 1351, 1261, 1211,
˜
1161, 1098, 1052, 957, 812, 663 cm–1. HRMS (ESI): calcd. for
C22H37N2O3S [M + H]+ 409.2519; found 409.2522.
(؎)-cis- and (؎)-trans-{3-Benzyl-1-[(3,5-di-tert-butylphenylsulfonyl)-
pyrrolidin-2-yl]methoxy}-2,2,6,6-tetramethylpiperidine (cis-6e and
trans-6e): Table 3, Entry 10. Cu(OTf)2 (7.0 mg, 0.019 mmol,
0.2 equiv.) and bis(oxazoline) 3 (4.3 mg, 0.024 mmol, 0.25 equiv.)
were allowed to complex in CF3Ph (0.7 mL) in a 100 mL round-
bottomed flask at 60 °C for 2 h. The heat was removed, and the
resulting room-temperature solution was treated with TEMPO
(44 mg, 0.282 mmol, 3 equiv.), K2CO3 (13 mg, 0.094 mmol,
1 equiv.) and a solution of sulfonamide 5e (40 mg, 0.094 mmol,
1 equiv.) in CF3Ph (0.3 mL). The reaction mixture was heated to
120 °C (oil-bath temp.) under O2 (1 atm, balloon, see above) for
24 h. Filtration of the cooled solution through an SiO2 plug
(washed with Et2O) and removal of the solvent in vacuo afforded
the crude product. Purification by flash chromatography on SiO2
(5% EtOAc in hexanes) gave a 14:1 trans/cis mixture of pyrrolidines
6e (46 mg, 83% yield). The diastereomers were further separated
by HPLC (5% EtOAc in hexanes); (Ϯ)-cis-6e eluted first.
Major Pyrrolidine (؎)-trans-6e was obtained as a clear, colorless
1
oil. H NMR (500 MHz, CDCl3): δ = 7.72 (s, 2 H), 7.67 (s, 1 H),
7.19 (t, J = 7.0 Hz, 2 H), 7.13 (t, J = 7.5 Hz, 1 H), 6.83 (d, J =
7.5 Hz), 3.96 (dd, J = 9.0, 3.5 Hz, 1 H), 3.84 (dd, J = 9.5, 8.0 Hz,
1 H), 3.46 (m, 1 H), 3.36 (m, 2 H) 2.49 (m, 1 H), 2.29 (dd, J =
14.0, 7.0 Hz, 1 H), 1.89 (m, 1 H), 1.76 (dd, J = 13.5, 8.5 Hz, 1 H),
1.40–1.49 (m, 6 H), 1.36 (s, 18 H), 1.27 (m, 1 H), 1.18 (s, 3 H), 1.15
[4] Recent metal-catalyzed intramolecular aminohalogenations:
Pd-catalyzed: a) M. R. Manzoni, T. P. Zabawa, D. Kasi, S. R.
Chemler, Organometallics 2004, 23, 5618–5621; b) A. W. Lei,
X. Y. Lu, G. S. Liu, Tetrahedron Lett. 2004, 45, 1785–1788; c)
F. E. Michael, P. A. Sibbald, B. M. Cochran, Org. Lett. 2008,
Eur. J. Org. Chem. 2011, 3679–3684
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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