Organocatalytic asymmetric ring-opening of aziridines

Article abstract of DOI:10.1039/b812369a

The organocatalytic ring-opening of N-tosyl protected aziridines by β-ketoesters under chiral PTC-conditions, leading to the formation of optically active aminoethyl functionalised compounds with up to 99% ee, has been developed.

Full text of DOI:10.1039/b812369a

Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is (c) The Royal Society of Chemistry 2008
Organocatalytic Asymmetric Ring-Opening of Aziridines
Marcio W. Paixão, Martin Nielsen, Christian Borch Jacobsen and Karl Anker Jørgensen*
Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
e-mail: kaj@chem.au.dk
Supporting Information
Contents
General Methods ………………………………………………………
Materials …..…..…………………………….……………………….
page S2
page S2
page S2
page S3
page S6
General Procedure for the Aziridine Ring-opening …...………………...
Data for Products 4 ....................................................................................
Spectra ......…………………………………………..……………………
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General Methods. NMR spectra were acquired on a Varian AS 400 spectrometer, running at 400 and
100 MHz for 1H and 13C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent
signals (CHCl3, 7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for. 13C NMR spectra were acquired on a broad
band decoupled mode. Mass spectra were recorded on a Micromass LCT spectrometer using electrospray
(ES+) ionization techniques. Analytical thin layer chromatography (TLC) was performed using pre-coated
aluminium-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation or KMnO4
dip. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. The enantiomeric excess (ee) of
the products was determined by chiral stationary phase HPLC (Daicel Chiralpak AD or Daicel Chiralcel
OD columns). Racemic samples were prepared using BEMP or TBAI as the catalyst.
Materials. Analytical grade solvents and commercially available reagents were used as received. For
flash chromatography (FC) silica gel was purchased from Fluka (Silica gel 60, 230-400 mesh). The
catalyst 3c,1 nucleophiles 1a-h2 and aziridines 2a-c3 were synthesised according to literature procedures.
General Procedure for the Organocatalytic Aziridine Ring-opening:
To a vial equipped with a magnetic stirring bar was added the phase-transfer catalyst 3 (6 mol%, 0.006
mmol), nucleophile 1 (0.2 mmol) and aziridine 2 (0.1 mmol) in a 7:1 mixture of o-xylene and CHCl3 (1.5
mL) and cooled to 2 oC when necessary. The reaction was started by addition of an aqueous solution of an
appropriate base (0.4 mL, see Table 2 in the article). The reaction was stirred for an appropriate amount
of time (see below) followed by removal of the aqueous phase and concentration of the organic phase.
Purification by FC (EtOAc/hexane 1:9 to 3:7) afforded the pure product.
1 See e.g.: a) B. Lygo and P. G. Wainwright, Tetrahedron, 1999, 55, 6289. b) T. B. Poulsen, L. Bernadi, J. Alemán, J.
Overgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 441.
2For the preparation of 1a and 1b see: a) J. Alemán, E. Reyes, B. Richter, J. Overgaard and K. A. Jørgensen, Chem. Commun.,
2007, 3921. For 1c, 1d and 1e see: b) H. O. House and C. B. Hudson, J. Org. Chem., 1970, 35, 647. For 1f see: c) L. A.
Carpino, J. Am. Chem. Soc., 1960, 82, 2725 and according to reference 1b. Subsequent Bu2SnO catalyzed transesterfication to
the t-butyl ester was done as described by: d) M. Nakajima, S.Yamamoto, Y. Yamaguchi, S. Nakamura, S. Hashimoto,
Tetrahedron, 2003, 59, 7307 when necessary. 1g and 1h was prepared from the commercially available methyl esters as
described in reference 2d.
3 A. L. Braga, M. W. Paixão, D. S. Lüdtke, C. C. Silveira and O. E. D. Rodrigues, Org. Lett., 2003, 5, 2635.
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Data for Compounds 4:
(S)-tert-Butyl 2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(4a):
O
Prepared according to the general procedure (reaction time 12 h), as white
O
crystals. Ee = 97%. Isolated yield = 87%. 1H NMR (CDCl3) δ 7.63 (d, J = 8.11
O
MeO
4a
NHTs
Hz, 2H), 7.59 (d, J = 8.49 Hz, 1H), 7.21 (d, J = 6.56 Hz, 2H), 6.84 (d, J = 8.39
Hz, 2H), 4.81 (t, J = 6.0 Hz, 1H), 3.83 (s, 3H), 3.46 (d, J = 17.3 Hz, 1H), 3.04-
2.96 (m, 2H), 2.91 (d, J = 17.3 Hz, 1H), 2.33 (s, 3H), 2.15-2.09 (m, 1H), 1.92-1.87 (m, 1H), 1,28 (s, 9H).
13C NMR (CDCl3) δ 200.7, 170.3, 166.1, 156.0, 143.5, 137.0, 129.9 (2), 128.1, 127.2 (2), 126.7, 116.2,
109.5, 82.5, 60.3, 55.9, 40.0, 37.4, 34.2, 27.9 (3), 21.7. HRMS calc.:C24H29NO6SNa+ 482.1603; found:
482.1607. The ee was determined by HPLC using two Chiralpak OD columns [hexane/iPrOH (85:15)];
flow rate 0.5 mL/min; τmajor = 82.8 min, τminor = 93.1 min (97% ee). [α]Drt +12.2o (c = 2.0, CH2Cl2).
(S)-tert-Butyl 5,6-dimethoxy-2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-
2-carboxylate (4b):
Prepared according to the general procedure (reaction time 12 h), as white
crystals. Ee = 90%. Isolated yield = 86%. 1H NMR (CDCl3) δ 7.63 (d, J = 8.25
Hz, 2H), 7.21 (d, J = 7.26 Hz, 2H), 7.06 (s, 1H), 6.79 (s, 1H), 4.78 (t, J = 6.0
Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.42 (d, J = 17.4 Hz, 1H), 3.09-2.92 (m,
13
2H), 2.88 (d, J = 17.5 Hz, 1H), 2.34 (s, 3H), 2.21-2.05 (m, 1H), 1.99-1.84 (m, 1H), 1,27 (s, 9H). C
NMR (CDCl3) δ 213.2, 170.4, 156.3, 149.9, 148.5, 143.5, 137.0, 129.9 (2), 127.6, 127.2 (2), 107.3, 105.1,
82.5, 60.3, 56.5, 56.3, 40.0, 37.3, 34.3, 27.9 (3), 21.7. HRMS calc.:C25H31NO7SNa+ 512.1719; found:
512.1710. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (80:20)]; flow
rate 1.0 mL/min; τminor = 37.4 min, τmajor = 50.2 min (90% ee). [α]Drt +36.1o (c = 0.1, CH2Cl2)
(S)-tert-Butyl 5-chloro-2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (4c):
O
Prepared according to the general procedure (reaction time 12 h), as yellow oil.
Ee = 93%. Isolated yield = 83%. 1H NMR (CDCl3) δ 7.06 (t, J = 7.88 Hz, 2H),
7.38 (s, 1H), 7.30 (d, J = 8.18 Hz, 1H), 7.25 (d, J = 8.6 Hz, 3H), 4.65 (bs, 1H),
O
O
Cl
4c
NHTs
3.47 (d, J = 17.2 Hz, 1H), 3.09-2.87 (m, 3H), 2.34 (s, 3H), 2.22-2.08 (m, 1H),
13
1.98-1.83 (m, 1H), 1,28 (s, 9H). C NMR (CDCl3) δ 201.3, 169.7, 154.3, 143.6, 142.2, 136.9, 133.5,
129.9 (2), 128.9, 127.2 (2), 126.7, 126.1, 83.2, 60.3, 35.9, 37,0, 34.0, 27.9 (3), 21.7. HRMS
calc.:C23H26ClNO7SNa+ 486.1118; found: 486.1122. The ee was determined by HPLC using a Chiralpak
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AD column [hexane/iPrOH (80:20)]; flow rate 1.0 mL/min; τminor = 23.6 min, τmajor = 33.3 min (93% ee).
[α]Drt +58o (c = 1.0, CH2Cl2).
(S)-tert-Butyl 2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(4d):
O
Prepared according to the general procedure (reaction time 12 h), as colourless oil.
Ee = 87%. Isolated yield 84%. 1H NMR (CDCl3) δ 7.64 (dd, J1 = 8.0, J2 = 15.7 Hz,
3H), 7.56 (t, J = 7.4, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.33
(d, J = 8.1 Hz, 2H), 4.65 (t, J = 6.0 Hz, 1H), 3.51 (d, J = 17.2 Hz, 1H), 3.13-2.81
O
O
4d
NHTs
13
(m, 3H), 2.34 (s, 3H), 2.21-2.02 (m, 1H), 2.00-1.82 (m, 1H), 1,28 (s, 9H). C
NMR (CDCl3) δ 202.7, 170.1, 152.9, 143.3, 137.2, 135.6, 135.0, 129.9 (2), 128.0, 127.2 (2), 126.5, 125.0,
82.7, 60.9, 40.1, 35.5, 34.1, 27.9 (3), 21.7. HRMS calc.:C23H27NO5SNa+ 452.1508; found: 452.1506. The
ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (80:20)]; flow rate 1.0
mL/min; τminor = 23.4 min, τmajor = 29.9 min (87% ee). [α]Drt +7.0o (c = 2.0, CH2Cl2).
(S)-Methyl
2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(4e):
O
Prepared according to the general procedure (reaction time 12 h), as colourless oil.
O
Ee = 70%. Isolated yield 89%. 1H NMR (CDCl3) δ 7.72-7.52 (m, 3H), 7.40 (d, J =
O
7.7 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 4.65 (t, J = 6.0 Hz,
4e
NHTs
1H), 3.58 (bs, 3H), 3.10-2.91 (m, 4H), 2.34 (bs, 3H), 2.27-2.14 (m, 1H), 2.04-1.87
(m, 1H). 13C NMR (CDCl3) δ 202.2, 171.6, 152.9, 143.6, 137.0, 135.9, 134.8, 129.9 (2), 128.2, 127.2 (2),
126.6, 125.2, 59.1, 53.2, 39.9, 37.3, 34.6, 21.7. HRMS calc.:C20H21NO5SNa+ 410.1038; found: 452.1025.
The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (80:20)]; flow rate 1.0
mL/min; τmajor = 41.0 min, τminor = 50.0 min (70% ee). [α]Drt +26.8o (c = 1.0, CH2Cl2).
tert-Butyl
1-(2-(4-methylphenylsulfonamido)ethyl)-2-oxo-2,3-dihydro-1H-indene-1-carboxylate
(4g):
Prepared according to the general procedure (reaction time 12 h), as colourless oil.
1
Ee = 76%. Isolated yield = 74%. H NMR (CDCl3) δ 7.2 (d, J = 8.2 Hz, 2H), 7.37-
O
O
NHTs
6.98 (m, 6H), 4.26 (t, J = 6 Hz, 1H), 3.66 (d, J = 22.5 Hz, 1H), 3.46 (d, J = 22.5 Hz,
1H), 2.86-2.64 (m, 2H), 2.42-2.27 (m, 4H), 2.26 – 2.19 (m, 1H), 1.22 (s, 9H) . 13C
NMR (CDCl3) δ 213.2, 169.0, 143.6, 139.9, 137.6, 136.7, 129.8 (2), 128.9, 128.1,
O
4g
127.2 (2), 125.5, 123.8, 83.0, 64.8, 43.5, 39.5, 32.8, 28.0, 27.8 (3), 21.7. HRMS calc.:C23H27NO5SNa+
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452.1508; found: 452.1512.The ee was determined by HPLC using a Chiralpak AD column
rt
[hexane/iPrOH (80:20)]; flow rate 1.0 mL/min; τmajor = 17.3 min, τminor = 18.3 min (76% ee). [α]D -4.8o
(c = 0.6, CH2Cl2).
(S)-tert-Butyl 1-(2-(4-methylphenylsulfonamido)ethyl)-2-oxocyclopentanecarboxylate (4h):
O
Prepared according to the general procedure (0.5 mL of o-xylene/CHCl3 (7:1) used as
O
1
solvent, reaction time 72 h) as colourless oil. Ee = 77%. Isolated yield = 53%. H
O
NMR (CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.86 (t, J = 6.0
4h
NHTs
Hz, 1H), 3.06 – 3.00 (m, 2H), 2.45 – 2.34 (m, 2H), 2.42 (s, 3H), 2.30 – 2.21 (m, 1H),
2.04 – 1.76 (m, 5H), 1.39 (s, 9H) . 13C NMR (CDCl3) δ 215.6, 170.5, 143.3, 136.7, 129.8 (2C), 127.1
(2C), 82.6, 59.6, 39.6, 37.6, 33.8, 32.7, 27.8 (3C), 21.5, 19.6. HRMS calc.: C19H27NO5SNa+ 404.1502;
found: 404.1516. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (92:8)];
flow rate 1.0 mL/min; τminor = 66.6 min, τmajor = 74.1 min (77% ee). [α]Drt +1.2o (c = 1.0, CH2Cl2).
N-tert-Butyl-2-(2-(4-methylphenylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxamide
(4i):
Prepared according to the general procedure (reaction time 20 h) as white crystals. Ee
O
O
= 23%. Isolated yield = 82%. 1H NMR (CDCl3) δ 7.77 – 7.70 (m, 3H), 7.64 (t, J = 7.6
N
H
Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H),
4i
NHTs
7.07 (s, 1H), 4.94 (s, 1H), 3.91 (d, J = 18 Hz, 1H), 3.16 – 2.95 (m, 3H), 2.41 (s, 3H), 2.14 – 2.07 (m, 1H),
1.93 – 1.86 (m, 1H), 1.28 (s, 9H). 13C NMR (CDCl3) δ 207.3, 168.0, 153.3, 143.4, 136.7, 136.3, 134.3,
129.7 (2C), 127.8, 127.0 (2C), 126.7, 124.6, 59.5, 51.4, 40.3, 39.5, 36.3, 28.4 (3C), 21.5. HRMS calc.:
C23H28N2O4SNa+ 451.1662; found: 451.1647. The ee was determined by HPLC using a Chiralpak AD
column [hexane/iPrOH (70:30)]; flow rate 1.0 mL/min; τmajor = 10.1 min, τminor = 20.3 min (23% ee).
[α]Drt -5.8o (c = 0.12, CH2Cl2).
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8.5
8.0
7.5
7.0
6.5
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4.5
f1 (ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1H NMR (400MHZ, CDCl3) Spectrum of 4a
13C NMR (100MHZ, CDCl3) Spectrum of 4a
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8.0
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f1 (ppm)
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0.0
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1H NMR (400MHZ, CDCl3) Spectrum of 4b
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f1 (ppm)
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13C NMR (100MHZ, CDCl3) Spectrum of 4b
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1H NMR (400MHZ, CDCl3) Spectrum of 4c
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13C NMR (100MHZ, CDCl3) Spectrum of 4c
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f1 (ppm)
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1H NMR (400MHZ, CDCl3) Spectrum of 4d
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f1 (ppm)
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13C NMR (100MHZ, CDCl3) Spectrum of 4d
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f1 (ppm)
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1H NMR (400MHZ, CDCl3) Spectrum of 4e
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13C NMR (100MHZ, CDCl3) Spectrum of 4e
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1H NMR (400MHZ, CDCl3) Spectrum of 4g
13C NMR (100MHZ, CDCl3) Spectrum of 4g
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1H NMR (400MHZ, CDCl3) Spectrum of 4h
13C NMR (100MHZ, CDCl3) Spectrum of 4h
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1H NMR (400MHZ, CDCl3) Spectrum of 4i
13C NMR (100MHZ, CDCl3) Spectrum of 4i
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