Stereoselective Synthesis of cis,cis-Configured Perhydroquinoxaline-5-Carbonitrile from Cyclohex-2-en-1-ol

Article abstract of DOI:10.1002/jhet.2322

cis,cis-Configured perhydroquinoxaline-5-carbonitrile 10 was synthesized stereoselectively by ditosylation of trans,cis-2,3-dihydroxycyclohexane-1-carbonitrile 4 and subsequent reaction with ethylenediamine. The diol precursor 4 was stereoselectively obtained by regioselective opening of the epoxide 3 with KCN in water avoiding hazardous Et₂AlCN.

Full text of DOI:10.1002/jhet.2322

Month 2015
Stereoselective Synthesis of cis,cis-Configured Perhydroquinoxaline-5-
Carbonitrile from Cyclohex-2-en-1-ol
Adrian Schulte, Susumu Saito, and Bernhard Wünsch *
a
b
a,c
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
c
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster,
Corrensstr. 48, 48149 Münster, Germany
*
E-mail: wuensch@uni-muenster.de
Additional Supporting Information may be found in the online version of this article.
Received May 27, 2014
DOI 10.1002/jhet.2322
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
cis,cis-Configured perhydroquinoxaline-5-carbonitrile 10 was synthesized stereoselectively by ditosylation of
trans,cis-2,3-dihydroxycyclohexane-1-carbonitrile 4 and subsequent reaction with ethylenediamine. The diol pre-
cursor 4 was stereoselectively obtained by regioselective opening of the epoxide 3 with KCN in water avoiding
2
hazardous Et AlCN.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
conversion of the epoxide 3 into the diol 4 using Et AlCN at
2
rt with 65% yield [11]. Furthermore amines are able to open
Perhydroquinoxalines have been widely employed in
medicinal chemistry, e.g. as δ opioid receptor [1] and
i
epoxides regioselectively when promoted with Ti(O Pr) [12].
4
Epoxide ring-opening in water is an established method
with similar regioselectivity as under Lewis acid-promoted
conditions [13]. We thus aimed at replacing the hazardous
5
-HT receptor ligands [2], cholinesterase inhibitors [3],
1
and P2X7 receptor antagonists [4]. Compounds with this
heterocycle have also been used for the treatment of de-
pression [5], type 2 diabetes [6], Alzheimer’s disease and
Down’s syndrome [7], as well as autoimmune diseases
8]. Recently, the trans,trans-configured 5-pyrrolidinyl-
substituted perhydroquinoxaline derivative 1 was demon-
organometallic reagent Et AlCN with KCN in water.
2
Performing the epoxide opening with amines in water
should also avoid the Ti(IV)-species. The reaction of epoxide
[
3
5
with pyrrolidine in water gave a quantitative yield of aminodiol
with high regio- and diastereoselectivity as well as high
strated to exhibit high κ opioid receptor affinity (K = 9.3
i
reproducibility. However, synthesis of the nitrile 4 required
some optimization. Finally it was found that a biphasic mixture
of water and ethyl acetate at a slightly elevated temperature
nM) [9].
This result motivated us to investigate type I compounds
by variation of, first, the relative configuration of the 5-
aminoquinoxaline scaffold and, second, the nature of the
substituent in 5-position. Whereas the cis,cis-configuration
of the scaffold could give insight into the dependence of
the κ affinity on the relative configuration, the introduction
of a pyrrolidinone or a cyano moiety in 5-position could al-
low late-stage diversification of the substrates.
The perhydroquinoxalines I are retrosynthetically derived
from trans,cis-configured ditosylates II and ethylenediamine
and II is further traced back to trans,cis-configured diols III.
The synthesis of piperazines by reaction of ethylene ditosylates
with ethylenediamine has not yet been reported (Fig. 1).
(40°C) provided the cyanodiol 4 in 62% yield, which is close
to the yield reported by Benedetti et al. using Et AlCN.
2
Despite a broad screening of reaction conditions and in con-
trast to other epoxides [14], deprotonated pyrrolidin-2-one did
not react with the epoxide 3, even after addition of the Lewis
acid Ti(Oi-Pr) . However, the synthesis of the diol 6 was
4
achieved by dihydroxylation of the alkene 7, which was pre-
pared by deprotonation of pyrrolidin-2-one with NaH and
subsequent reaction with 3-bromocyclohex-1-ene [15]. Reac-
tion of 7 with KMnO and MgSO at À25°C, similar to the
4
4
method of Kresze and Kysela [16], furnished the diol 6 with
51% yield as a 7:3 mixture of the trans,cis- (6A) and cis,
cis-configured (6B) diastereomers (Scheme 1).
Conversion of the diol 5 with p-toluenesulfonyl (tosyl)
chloride was complete after 2.5 d as monitored by tlc.
However, after aqueous work-up, the diol 5 was reisolated
with 96% yield. It is therefore postulated that an intermediate
N-tosylammonium salt was formed [17], which is probably
due to the high nucleophilicity of the pyrrolidine N-atom.
SYNTHESIS
Cyclohex-2-en-1-ol (2) reacted with monoperoxyphthalic
acid (MPPA) in aqueous solution applying the method of Ye
et al. [10] to stereoselectively afford the cis-configured
epoxyalcohol 3 in 73% yield. Benedetti et al. reported the
©
2015 HeteroCorporation

A. Schulte, S. Saito, and B. Wünsch
Vol 000
Figure 1. Development of target compounds I from the κ agonist 1 and retrosynthetic analysis.
The diol 6 reacted with tosyl chloride to give the epoxide
stereospecifically in 75% yield. This reverse transforma-
Scheme 2. Synthesis of the perhydroquinoxaline 10 from the diol 4.
3
tion of the diol 6 into the epoxide 3 is explained by
tosylation of the lactam O-atom, followed by intramolecular
nucleophilic substitution of the pyrrolidone group by the
vicinal OH group. Reaction of the diol 6 with other
electrophiles, e.g. intermediate sulfonium ylides generated
under conditions of a Swern oxidation, also led to stereo-
specific formation of the epoxide 3, which was isolated in
high yields. This result indicates the high reactivity of the
pyrrolidin-2-one moiety against electrophiles.
The cyanodiol 4 reacted with thionyl chloride to give the
cyclic sulfite 9 in 69% yield. However, reaction of cyclic
sulfite 9 with ethylenediamine only led to decomposition.
Therefore, the cyanodiol 4 was treated with tosyl chloride
to afford the ditosylate 8 in 38% yield, which was reacted
with ethylenediamine in refluxing THF to give the desired
cis,cis-configured perhydroquinoxaline-5-carbonitrile (10)
in 42% yield (Scheme 2).
synthesis depends strongly on the nature of the substituent in
3-position of the cyclohexane-1,2-diol. Whereas pyrrolidine
and pyrrolidin-2-one substituted cyclohexanediols 5 and 6 react
with electrophiles under N-tosylation (desactivation) and actam
tosylation (pyrrolidone elimination), respectively, the cyano
group allowed the transformation of both OH-groups of 4 into
tosyloxy leaving groups. Thus, cis,cis-configured perhydro-
quinoxaline-5-carbonitrile (10) was prepared stereoselectively,
which will be used as a precursor in the synthesis of new
quinoxaline-based κ agonists.
CONCLUSION
The successful synthesis of the quinoxalinecarbonitrile 10
demonstrates that cis,cis-configured 5-substituted perhydro-
quinoxalines are accessible by double nucleophilic substitution
of 1,2-ditosylates with ethylenediamine. However, the
Scheme 1. Synthesis of the diols 4, 5, and 6.
EXPERIMENTAL
General.
All commercially available reagents were used
without further purification. THF was dried by distillation over
sodium. All reactions were carried out under nitrogen
atmosphere. The reactions were monitored by thin layer
chromatography (tlc) using silica gel-coated aluminium plates
(
4
Merck KGaA, 60F254) and visualized with KMnO . 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 R value.
All new compounds gave satisfactory spectroscopic analyses
f
1
13
(
IR, H NMR, C NMR, and HRMS). NMR spectra were
recorded on a 400-MHz spectrometer (Varian Mercury® Plus
1
4
00) and on a 600-MHz spectrometer (Jeol ECA 600). H NMR
spectra are reported in parts per million (δ) relative to TMS
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
cis,cis-Perhydroquinoxalinecarbonitrile
1
calculated from the residual solvent signals. Data for H NMR
(172 mg, 1.09 mmol, 1.8 equiv.) in H O (4.0 mL) was added
2
spectra are as follows: chemical shift δ (ppm), multiplicity
dropwise over a period of 2 h. The resulting mixture was
stirred under slow warming to ambient temperature for 16 h,
then diluted with iso-propanol (2 mL) and filtered (paper,
grade 388). The residue was washed with ethanol. The
filtrate was concentrated under reduced pressure, and the
(
s = singlet, b = broad, d = doublet, t = triplet, q = quartet,
dd = doublet of doublets, and m = multiplet), coupling constant J
1
3
(
Hz), and relative integration. C 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 microTOF-QII (APCI,
residue was dissolved in CH Cl2 (10 mL). The solution was
dried (Na SO ) and concentrated under reduced pressure.
2 4
2
TM
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
The residue was purified by fc (d = 3 cm, l = 10 cm,
V = 20 mL, cyclohexane:ethyl acetate = 1:0 ➔ 7:1 ➔ 1:1 ➔
0:1 ➔ ethyl acetate:methanol = 19:1, R = 0.50 (tlc, ethyl
f
4
acetate:methanol = 1:1, detection: KMnO )) to afford a 7:3
mixture of the diastereomers 6A and 6B (61 mg, 51%) as a
À1
1
reported as wave numbers υ (cm ). Melting points were
pale yellow oil. Two sets of signals ( H NMR intensity ratio
TM
measured using a Stuart
SMP3 apparatus in capillary tubes
6A:6B = 7:3) are seen in the spectra originating from two
1
sealed on one side and are uncorrected.
diastereomers. H NMR (400MHz, CDCl ): δ [ppm]= 1.32–1.55
3
(
4).
1RS,2RS,3SR)-2,3-Dihydroxycyclohexane-1-carbonitrile
(m, 3H, 4-CH2,cycl, 5-CH2,cycl, 6-CH2,cycl), 1.56–1.87 (m, 2H,
5-CH2,cycl, 6-CH2,cycl), 1.90–2.10 (m, 3H, 4-CH2,py, 4-CH2,cycl),
2.35–2.43 (m, 1H, 3-CH2,py), 2.42–2.49 (m, 1H, 3-CH2,py), 3.40
(t, J = 7.1 Hz, 2H, 5-CH2,py), 3.49 (dd, J = 10.8/3.3Hz, 0.7x1H,
2-CHcycl, A), 3.62 (dd, J = 5.8/2.1 Hz, 0.3x1H, 2-CHcycl, B), 3.97
(ddd, J = 5.8/5.6/4.6Hz, 0.3x1H, 1-CHcycl, B), 4.06 (t, J = 2.1 Hz,
(
(
(
KCN (251 mg, 3.85 mmol, 4.0 equiv.) and NaHCO
3
323 mg, 3.85 mmol, 4.0 equiv.) were dissolved in H
5 mL), and a solution of the epoxide 3 (110 mg, 0.964 mmol,
.0 equiv.) in ethyl acetate (2 mL) was added. The mixture
was stirred at 40°C for 24 h. The layers were separated. The
aqueous layer was saturated with NaCl and extracted with
2
O
1
0.3x1H, 3-CHcycl, B), 4.15 (dd, J = 5.6/3.3 Hz, 0.7x1H, 3-CHcycl
,
CH
2
Cl
2
(4 × 7 mL). The combined organic layers were dried
A), 4.25 (ddd, J = 12.2/10.8/4.1 Hz, 0.7x1H, 1-CH c1y cl, A). Signals
3 1
(
Na SO ) and concentrated under reduced pressure. The
for the OH protons are not seen in the spectrum. C{ H} NMR
(100 MHz, CDCl ): δ [ppm] = 18.1 (C-4 , A), 18.2 (C-4 , B),
2
4
residue was purified by fc (d = 5 cm, l = 5 cm, V = 20 mL,
cyclohexane:ethyl acetate = 1:0 ➔ 7:1 ➔ 7:3 ➔ 0:1, R = 0.22
tlc, cyclohexane:ethyl acetate = 1:1, detection: Hanessian’s
3
py
py
f
18.6 (C-5cycl, B), 18.7 (C-5cycl, A), 27.6 (C-6cycl, B), 28.7
(C-6cycl, A), 30.2 (C-4cycl, B), 30.9 (C-4cycl, A), 31.5 (C-3py, B),
31.8 (C-3 , A), 43.4 (C-5 , A), 43.6 (C-5 , B), 51.7 (C-1cycl,
(
stain)) to afford the diol 4 (84 mg, 62%) as a colorless solid,
mp 82–83°C. See supplementary information and report [18]
for spectroscopic data.
py
py
py
A), 58.1 (C-1cycl, B), 70.1 (C-3cycl, A), 71.2 (C-2cycl, B), 72.4
(C-2cycl, A), 72.7 (C-3cycl, B), 175.3 (C-2py, B), 177.2 (C-2py, A).
À1
(
1RS,2SR,3RS)-3-(Pyrrolidin-1-yl)cyclohexane-1,2-diol
The epoxide 3 (795 mg, 6.97 mmol, 1.0 equiv.) was
FT-IR (ATR): eυ[cm ] = 3410 (bs, O–H), 2936 (s, C–H), 2866 (s,
(
5).
C–H), 1690 (s, C = O). Exact mass (APCI): m/z = 200.1289 (calcd.
+
dissolved in H O (5 mL). Pyrrolidine (5.7 mL, 70 mmol, 10
200.1287 for C H NO [MH] ).
2
10 18
3
equiv.) was added, and the mixture was stirred for 3 d. The
solvent and excess pyrrolidine were removed under reduced
pressure, and the residue was dissolved in methanol. The
solution was dried (Na SO ), immobilized on silica gel, and
2 4
purified by fc (d = 8 cm, l = 2 cm, V = 65 mL, cyclohexane:
ethyl acetate = 1:0 ➔ 7:1 ➔ 1:1 ➔ 0:1 ➔ ethyl acetate:
methanol = 19:1 ➔ 7:1, R
iodine chamber)) to afford the diol 5 (1.27 g, 98%) as a red
oil.
(1RS,2SR,3SR)-3-Cyanocyclohexane-1,2-diyl bis(4-methylben-
zenesulfonate) (8).
The diol 4 (132 mg, 0.935 mmol, 1.0
equiv.) was dissolved in pyridine (1 mL), and, at 0°C,
4-methylbenzenesulfonyl chloride (178 mg, 0.935 mmol, 1.0
equiv.) was added. The mixture was warmed to ambient
temperature under stirring for 2 d. The mixture was diluted
with an aqueous solution of HCl (2 M, 5 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic layers
f
= 0.10 (tlc, methanol, detection:
1
H
NMR (600 MHz, CDCl
3
):
δ
[ppm] = 1.26 (td,
were dried (Na
2
SO
4
)
and concentrated under reduced
J = 13.3/3.5 Hz, 1H, 4-CH2,cycl,eq), 1.41 (tdd, J = 13.3/3.8/
pressure. The residue was purified by fc (d = 3 cm, l = 10 cm,
V = 20 mL, cyclohexane:ethyl acetate = 1:0 ➔ 39:1 ➔ 19:1 ➔
2
5
1
.8 Hz, 1H, 6-CH2,cycl,eq), 1.59 (tt, J = 13.3/3.4 Hz, 1H,
-CH2,cycl), 1.69 (tt, J = 13.3/3.8 Hz, 1H, 5-CH2,cycl),
.80–1.88 (m, 5H, 3-CH2,py, 4-CH2,py, 4-CH2,cycl,ax), 1.91
7:1, R
f
= 0.66 (tlc, cyclohexane:ethyl acetate = 1:1, detection:
Hanessian stain)) to afford the ditosylate 8 (160 mg, 38%) as
2
3
1
(
(
dd, J = 16.8 Hz, J = 14.5 Hz, 1H, 6-CH2,cycl,ax), 2.84–2.92
m, 4H, 2-CH2,py, 5-CH2,py), 3.14 (ddd, J = 12.0/10.5/3.5 Hz,
a
colorless oil.
H
NMR (600 MHz, CDCl3):
δ
[ppm] = 1.57–1.73 (m, 4H, 4-CH , 5-CH , 6-CH ), 2.00–2.13
2
2
2
1
H, 3-CHcycl), 3.52 (dd, J = 10.5/3.0 Hz, 1H, 2-CHcycl), 4.16
(m, 2H, 4-CH
2
, 6-CH
2
), 2.44 (s, 6H, CH
3
), 3.17 (bs, 1H,
1
3
1
(
d, J = 3.0 Hz, 1H, 1-CHcycl), 4.96 (s, 2H, OH). C{ H}
NMR (150 MHz, CDCl ): δ [ppm] = 19.2 (C-5cycl), 22.4
C-4cycl), 23.7 (C-3 , C-4 ), 29.9 (C-6cycl), 48.5 (C-2py,
3-CH), 4.43 (d, J = 8.2 Hz, 1H, 2-CH), 4.86 (bs, 1H, 1-CH),
7.33 (d, J = 8.9 Hz, 2H, 3-CHar, 5-CHar), 7.34 (d, J = 8.6 Hz,
2H, 3-CHar, 5-CHar), 7.70 (d, J = 8.9 Hz, 2H, 2-CH ,
3
(
py
py
ar
1
3
1
C-5 ), 60.0 (C-3cycl), 69.0 (C-1cycl), 72.4 (C-2cycl). FT-IR
6-CH ), 7.76 (d, J = 8.6 Hz, 2H, 2-CH , 6-CH ). C{ H}
py
ar
ar
ar
À1
(
ATR): eυ[cm ] = 3368 (bs, O–H), 2934 (s, C–H), 2871 (s,
NMR (150 MHz, CDCl
3
):
δ
[ppm] = 18.6 (C-4), 21.8
C–H), 2819 (s, C–H). Exact mass (APCI): m/z = 186.1546
(
(CH
76.6 (C-2), 119.1 (C ≡ N), 128.0 (C-2ar, C-6ar), 128.5 (C-2ar
C-6 ), 130.1 (C-3 x2, C-5 x2), 132.0 (C-4 ), 133.1 (C-4 ),
3
x2), 27.0 (C-5), 28.1 (C-6), 30.7 (C-3), 76.1 (C-1),
+
calcd. 186.1494 for C10
H
20NO
2
[MH] ).
,
1-[(1RS,2SR,3RS)- and (1RS,2RS,3SR)-2,3-Dihydroxycyclohex-
ar
ar
ar
ar
ar
1
0
-yl]pyrrolidin-2-one (6A and 6B).
.605 mmol, 1.0 equiv.) was dissolved in ethanol (1.5 mL),
The alkene 7 (100 mg,
145.3 (C-1ar), 145.8 (C-1ar). FT-IR (NaCl plates): eυ
À1
+
[cm ] = 2960 (m, C–H), 2256 (m, C ≡ N). Exact mass
and the solution was cooled to À25°C. A solution of
(ESI ): m/z = 472.0876 (calcd. 472.0864 for C21
H
23NNaO
6
S
2
+
MgSO (124 mg, 1.03 mmol, 1.7 equiv.) and KMnO
4
4
[MNa] ).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Schulte, S. Saito, and B. Wünsch
Vol 000
1
3
1
(
2RS,3aRS,4RS,7aSR)-2-Oxo-3a,4,5,6,7,7a-hexahydrobenzo
(t, J = 6.6 Hz, 1H, 3-CH), 4.9 (bs, 2H, 1-NH, 4-NH). C{ H}
4
[
0
d]-[1,3,2λ ]dioxathiol-4-carbonitrile (9). The diol 4 (100 mg,
.708 mmol, 1.0 equiv.) and NEt (0.22 mL, 1.6 mmol, 2.2 equiv.)
were dissolved in abs. THF (10mL). At 0°C, thionyl chloride
77 μL, 1.1 mmol, 1.5 equiv.) was added dropwise, and the
mixture was stirred for 2 h at 0°C. H O (3 mL) was added, and the
resulting layers were separated. The aqueous layer was extracted
NMR (150 MHz, CDCl ): δ [ppm]= 19.6 (C-8), 23.1 (C-7), 27.6
(C-6), 39.8 (C-8a), 44.2 (C-2), 45.0 (C-4a), 52.9 (C-5), 62.0
3
3
À1
(C-3), 119.2 (C ≡ N). FT-IR (NaCl plates): eυ [cm ] = 3274 (bs,
+
(
NH), 2951 (s, C–H), 2214 (m, C ≡ N). Exact mass (ESI ):
+
m/z = 166.1352 (calcd. 166.1344 for C H N [MH] ).
9 16 3
2
with CH
dried (Na
2
Cl
2
(2× 10mL). The combined organic layers were
4
) and concentrated under reduced pressure. The
2
SO
Acknowledgment. This work was performed within the framework
of the International Research Training Group ‘Complex Functional
Systems in Chemistry: Design, Synthesis, and Applications’ in
collaboration with the University of Nagoya. Financial support of
this project by the IRTG Münster—Nagoya and the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
residue was purified by fc (d = 3 cm, l = 10 cm, V = 20mL,
cyclohexane:ethyl acetate = 1:0 ➔ 19:1 ➔ 7:1, R = 0.65 (tlc,
cyclohexane:ethyl acetate = 1:1, detection: KMnO
f
4
)) to afford a
7
:3 mixture of the diastereomers 9A and 9B (92 mg, 69%) as a
1
colorless oil. Two sets of signals ( H NMR intensity ratio A:
B = 7:3) are seen in the NMR spectra originating from two
diastereomers. H NMR (400 MHz, CDCl ): δ [ppm] = 1.49–1.66
1
3
(
m, 2H, 5-CH3
2
, 6-CH
2
), 1.66–1.82 (m, 1H, 6-CH
, B), 1.98 (ddd,
J = 15.9Hz, J = 12.2/3.9Hz, 0.7x1H, 7-CH , A), 2.10 (d,
2
), 1.86 (ddd,
2
2
J = 16.9Hz, J = 10.6/4.4Hz, 0.3x1H, 7-CH
2
3
REFERENCES AND NOTES
2
2
J = 11.6Hz, 0.7x1H, 5-CH , A), 2.19 (d, J = 14.3 Hz, 0.3x1H,
2
2
[1] Barn, D. R.; Bom, A.; Cottney, J.; Caulfield, W. L.; Morphy, J. R.
Bioorg Med Chem Lett 1999, 9, 1329.
5
-CH , B), 2.32 (d, J = 15.9 Hz, 0.7x1H, 7-CH , A), 2.39 (d,
2
2
2
J = 16.9Hz, 0.3x1H, 7-CH
2
, B), 2.58 (ddd, J = 12.4/8.9/3.3 Hz,
[
[
2] Howard, H. R. European Patent EP/0952154, 1999-10-27.
3] Rozengart, E. V.; Basova, N. E. J Evol Biochem Physiol 2001,
0
.7x1H, 4-CH, A), 3.39 (ddd, J = 12.5/9.4/3.8 Hz, 0.3x1H, 4-CH,
B), 4.57 (dd, J = 9.4/4.4 Hz, 0.3x1H, 3a-CH, B), 4.71 (d,
J = 4.4 Hz, 0.3x1H, 7a-CH, B), 4.82 (dd, J = 8.9/4.0 Hz, 0.7x1H,
3
7, 604.
[
4] Betschmann, P.; Carroll, W. A.; Ericsson, A. M.; Fix-Stenzel,
13
1
3
a-CH, A), 5.15 (d, J = 4.0 Hz, 0.7x1H, 7a-CH, A). C{ H}
S. R.; Hirst, G. C.; Josephsohn, N. S.; Li, B.; Perez-Medrano, A.;
Morytko, M. J.; Rafferty, P.; Chen, H. World Patent WO/2008005368,
008-01-10.
NMR (100 MHz, CDCl ): δ [ppm] = 18.4 (C-6, both), 25.3 (C-7,
3
2
major, A), 26.3 (C-5, major, A), 26.8 (C-5, minor, B), 27.0 (C-7,
minor, B), 32.9 (C-4, major, A), 33.5 (C-4, minor, B), 76.0 (C-3a,
major, A), 78.2 (C-3a, minor, B), 79.1 (C-7a, major, A), 81.2
[
5] Shinohara, T.; Sasaki, H.; Tai, K.; Ito, N. World Patent WO/
2
013137479, 2013-09-19.
[
6] Webster, S. C.; Seckl, J. R.; Walker, B. R.; Ward, P.; Pallin,
T. D.; Dyke, H. J.; Perrior, T. R. World Patent WO/2009112845,
009-09-17.
7] Thompson, L. A.; Kasireddy, P. World Patent WO/0174796,
2001-10-11.
[8] Eisenbarth, G.; Michels, A.; Nakayama, M.; Ostrov, D. World
(
C-7a, minor, B), 119.4 (C ≡ N, major, A), 119.7 (C ≡ N, minor,
À1
+
B). FT-IR (ATR): eυ [cm ] = 2951 (s, C–H), 2236 (m, C ≡ N),
2
1
203 (s, S = O). MS (EI ): m/z = 188 ([M + H], 9.7%), 139
[
(
[M À SO], 9.4%), 123 ([M À SO ], 21%), 110 ([M À SO À CH],
3
2
3
9
7
9%), 106 ([M À SO À OH], 37%), 95 ([M À SO À CO], 55%),
2
2
4 ([M À SO
8%), and 67 ([M À SO
4aRS,5RS,8aSR)-Decahydroquinoxaline-5-carbonitrile
10). The ditosylate 8 (130 mg, 0.289 mmol, 1.0 equiv.) was
dissolved in abs. THF (5mL) and ethylenediamine (38 μL,
.58 mmol, 2.0 equiv.) was added. The mixture was heated under
2
À CHO], 67%), 80 ([MÀ SO
2
À CHO À CH
2
],
Patent WO/2012162697, 2012-11-29.
2
À CHO À CH À CH], 100%).
2
[9] Bourgeois, C.; Schepmann, D.; Wünsch, B. World Patent WO/
2
1
1
009/08745, 2009-07-02.
10] Ye, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F. J Org Chem
997, 62, 3748.
(
[
(
[
11] Benedetti, F.; Berti, F.; Norbedo, S. Tetrahedron Lett 1999, 40,
0
041.
reflux for 5.5 h. After cooling to ambient temperature, the mixture
was filtered. Silica gel (100mg) was added, and the mixture was
concentrated under reduced pressure. The residue was purified by
fc (d = 3 cm, l = 3 cm, V = 100 mL, cyclohexane:ethyl acetate= 1:0
[
12] Nicolaou, K. C.; Peng, X.-S.; Sun, Y.-P.; Polet, D.; Zou, B.;
Lim, C. S.; Chen, D. Y.-K. J Am Chem Soc 2009, 131, 10587.
[13] Bonollo, S.; Lanari, D.; Vaccaro, L. Eur J Org Chem 2011,
2587.
[14] Buckle, D. R.; Eggleston, D. S.; Houge-Frydrych, C. S. V.;
Pinto, I. L.; Readshaw, S. A.; Smith, D. G.; Webster, R. A. B. J Chem
Soc Perkin Trans 1 1991, 2763.
➔
7:1 ➔ 0:100 ➔ ethyl acetate:methanol = 3:1 (500 mL), product
not detected by TLC, collection of the ethyl acetate:methanol
mixture is necessary) to afford the quinoxaline 10 (20 mg (42%)
1
[15] Schulte, A.; Saito, S.; Wünsch, B. Eur J Org Chem 2014,
749.
as
a
colorless oil.
H
NMR (600MHz, CDCl
3
):
δ
5
[
ppm] = 1.56–1.62 (m, 1H, 6-CH ), 1.68–1.72 (m, 1H, 8-CH ),
2
2
[
[
[
16] Kresze, G.; Kysela, E. Liebigs Ann Chem 1981, 202.
17] Schlegel, F. Ber Dtsch Chem Ges 1931, 64, 1739.
18] Boyd, D. R.; Sharma, N. D.; Berberian, M. V.; Dunne, K. S.;
1
2
8
3
.80–1.88 (m, 2H, 7-CH ), 1.92–1.94 (m, 2H, 6-CH , 8-CH ),
2 2 2
.88 (dd, J = 4.8/5.5 Hz, 1H, 4a-CH), 2.97 (d, J = 5.7 Hz, 1H,
a-CH), 3.25–3.31 (m, 1H, 5-CH), 3.42 (t, J = 6.6 Hz, 1H, 2-CH),
.45 (t, J = 6.8 Hz, 1H, 2-CH), 3.57 (t, J = 6.8 Hz, 1H, 3-CH), 3.67
Hardacre, C.; Kaik, M.; Kelly, B.; Malone, J. F.; McGregor, S. T.;
Stevenson, P. J Adv Synth Catal 2010, 352, 855.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet