Supporting Information
Stereoselective synthesis of cis,cis-configured
perhydroquinoxaline-5-carbonitrile from cyclohex-2-en-1-ol
Adrian Schulte,a Susumu Saito,b Bernhard Wünsch*a
a
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-
Universität Münster, Corrensstr. 48, 48149 Münster, Germany
b
Graduate School of Science and Institute for Advanced Research, Nagoya
University Chikusa, Nagoya 464-8602, Japan
*corresponding author: Tel.: +49-251-8333311; Fax: +49-251-8332144; E-mail:
wuensch@uni-muenster.de
Content
page
1. Instrumentation and chemicals
S2
2. Synthetic procedures
S3
3. 1H and 13C NMR spectra
S5
4. References
S11
S1
1. Instrumentation and chemicals
All commercially available reagents were used without further purification. CH 2Cl2
and THF were dried by distillation over CaH2 and sodium, respectively. DMSO was
dried over molecular sieves (4 Å). All reactions were carried out under nitrogen
atmosphere. The reactions were monitored by thin layer chromatography (tlc) using
silica gel-coated aluminium plates (Merck KGaA, 60 F254) and visualized with
KMnO4. Yields refer to chromatographically purified or distilled compounds. Flash
column chromatography (fc) was carried out using silica gel (Merck KGaA, 400 –
630 µm mesh) at medium pressure (1.5 bar). Parentheses include diameter d of the
column, stationary phase length l, fraction size V, eluent and Rf value. All new
compounds gave satisfactory spectroscopic analyses (IR, 1H NMR, 13C NMR, HRMS).
NMR spectra were recorded on a 400 MHz spectrometer (Varian Mercury® Plus 400)
and on a 600 MHz spectrometer (Jeol ECA 600). 1H NMR spectra are reported in
parts per million (δ) relative to TMS calculated from the residual solvent signals. Data
for 1H NMR spectra are as follows: chemical shift δ (ppm), multiplicity (s = singlet,
b = broad, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet),
coupling constant J (Hz) and relative integration.
13C
NMR spectra are reported in
parts per million (δ) relative to TMS calculated from the residual solvent signal. High
resolution mass spectra (HRMS) were obtained on a Bruker® Daltonics microTOFQIITM (APCI, ESI). Fragmentation mass spectra (EI) were obtained on a Thermo
Finnigan GCQ Finnigan MAT. Infrared (IR) spectra were recorded on an FT-IR
spectrometer (Jasco® FT/IR-480 plus) using attenuated total reflection (ATR)
technique or by transmission through NaCl plates (Jasco FT/IR-6100) and are
reported as wave numbers  (cm-1). Melting points were measured using a StuartTM
SMP3 apparatus in capillary tubes sealed on one side and are uncorrected.
S2
2. Synthetic procedures
2.1. (1RS,2RS,6SR)-7-Oxabicyclo[4.1.0]heptan-2-ol (3)1
Monoperoxyphthalic acid (700 mg, 3.84 mmol, 2.5 equiv.) was dissolved
O
in an aqueous solution of NaOH (0.16 M, 3.84 mmol, 2.5 equiv.) and the
OH
mixture was cooled to 0 °C. Cyclohex-2-ene-1-ol (0.15 mL, 1.54 mmol,
1.0 equiv.) was added dropwise. The mixture was allowed to slowly warm to ambient
temperature and stirred for 18 h. It was then saturated with NaCl, centrifuged and
decanted. The residue was washed with CH2Cl2 (2 x 10 mL) and the supernatant was
extracted with CH2Cl2 (5 x 10 mL). The combined organic layers were washed with
brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was
purified by fc (d = 8 cm, l = 5 cm, V = 20 mL, cyclohexane : ethyl acetate = 1 : 0 
37 : 3  0 : 1, Rf = 0.03 (tlc, cyclohexane : ethyl acetate = 1 : 1, detection: KMnO4))
to afford the epoxide 3 (128 mg, 73 %) as a colorless oil.
Spectroscopic data are identical to the reported data.2
2.2. (1RS,2RS,3SR)-2,3-Dihydroxycyclohexane-1-carbonitrile (4)
1H
CN
NMR (600 MHz, CDCl3): δ [ppm] = 1.47 – 1.63 (m, 4H, 4-CH2, 5-CH2,
OH
6-CH2), 1.91 (dd, J = 13.2 / 3.1 Hz, 1H, 4-CH2), 2.05 (d, J = 15.1 Hz, 1H,
OH
5-CH2), 2.90 (td, J = 8.9 / 2.7 Hz, 1H, 1-CH), 3.74 (d, J = 8.9 Hz, 1H, 2-
CH), 4.04 (d, J = 2.8 Hz, 1H, 3-CH). Signals for the OH protons were not seen in the
NMR (150 MHz, CDCl3): δ [ppm] = 18.3 (C-6), 27.2 (C-5), 29.9 (C4), 32.1 (C-1), 68.4 (C-3), 71.7 (C-2), 121.5 (C≡N). FT-IR (NaCl plates): υ~ [cm-1] =
spectrum.
13C{1H}
3427 (bs, O-H), 2939 (s, C-H), 2242 (s, C≡N). Exact mass (ESI+): m/z = 164.0719
(calcd. 164.0687 for C7H11NNaO2 [MNa]+).
Spectroscopic data are identical to the reported data.3
2.3. 1-[(1RS)-Cyclohex-2-enyl]-pyrrolidin-2-one (7)4
NaH (60 %-w/w suspension in mineral oil, 6.46 g, 161 mmol, 4.0 equiv.)
O
N
was suspended in abs. THF (200 mL). Pyrrolidin-2-one (15.5 mL,
201 mmol, 5.0 equiv.) was added dropwise and the mixture was stirred for
3 h until no more evolution of gas was observed. It was then concentrated
under reduced pressure and the residue was suspended in dry DMSO (100 mL). 3S3
Bromocyclohex-1-ene (6.50 g, 40.4 mmol, 1.0 equiv.) was added dropwise and the
resulting mixture was stirred for 19 h, then diluted with H2O (100 mL) and extracted
with ethyl acetate (5 x 50 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated under reduced pressure. The residue was purified
by fc (d = 8 cm, l = 15 cm, V = 100 mL, cyclohexane : ethyl acetate = 1 : 0  7 : 1 
3 : 1  7 : 3, Rf = 0.83 (tlc, ethyl acetate : methanol = 1 : 1, detection: KMnO4)) to
afford the olefin 7 (5.36 g, 80 %) as a colorless oil.
Spectroscopic data are identical to the reported data.5
S4
3. 1H and 13C NMR spectra
3.1. (1RS,2RS,3SR)-3-(Pyrrolidin-1-yl)cyclohexane-1,2-diol (5)
1H
NMR spectrum of the compound 5.
13C
NMR spectrum of compound 5.
S5
3.2.
(1RS,2SR,3RS)-
and
(1RS,2RS,3SR)-1-(2,3-Dihydroxycyclohex-1-
yl)pyrrolidin-2-one (6A and 6B)
6A
1H
6B
NMR spectrum of compounds 6A and 6B.
6A
13C
6B
NMR spectrum of compounds 6A and 6B.
S6
3.3.
(1RS,2SR,3SR)-3-Cyanocyclohexane-1,2-diyl
bis(4-methylbenzene-
sulfonate) (8)
1H
NMR spectrum of the compound 8.
13C
NMR spectrum of the compound 8.
S7
3.4.
(2RS,3aRS,4SR,7aSR)-2-Oxo-3a,4,5,6,7,7a-hexahydrobenzo[c]-[1,3,2]-
dioxathiol-4-carbonitrile (9)
1H
NMR spectrum of the compound 9.
13C
NMR spectrum of the compound 9.
S8
3.5. (4aRS,5RS,8aSR)-Decahydroquinoxaline-5-carbonitrile (10)
1H
NMR spectra of the comopund 10.
S9
13C
NMR spectrum of the compound 10.
S10
4. References
(1)
Ye, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem. 1997, 62, 3748.
(2)
Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc. 1970, 1374.
(3)
Boyd, D. R.; Sharma, N. D.; Berberian, M. V.; Dunne, K. S.; Hardacre, C.; Kaik,
M.; Kelly, B.; Malone, J. F.; McGregor, S. T., Stevenson, P. J. Adv. Synth.
Catal. 2010, 352, 855.
(4)
Schulte, A.; Saito, S.; Wünsch, B. J. Org. Chem. 2014, article submitted.
(5)
Tomioka, H.; Ooishi, T.; Takahashi, J.; Sasaki, M.; Hirata, N. European Patent
EP0128006 (A2); 1984-12-12.
S11