A new synthesis of amino acid-based enantiomerically pure substituted 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines

Article abstract of DOI:10.1039/c000029a

A new series of enantiomerically pure 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1, 2-a]quinoxalines were synthesized for the first time in twelve steps from 1-fluoro-2-nitrobenzene and S-amino acids with 13-20% overall yields. First use of intramolecular Mitsunobu cyclization for 1,2,3,4-tetrahydroquinoxalines followed by PPh₃/I₂/imidazole mediated 6-exo-tet cyclization were the key steps.

Full text of DOI:10.1039/c000029a

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A new synthesis of amino acid-based enantiomerically pure substituted
2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines†‡
Krishnananda Samanta and Gautam Panda*
Received 12th January 2010, Accepted 30th March 2010
First published as an Advance Article on the web 22nd April 2010
DOI: 10.1039/c000029a
A new series of enantiomerically pure 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines were
synthesized for the first time in twelve steps from 1-fluoro-2-nitrobenzene and S-amino acids with
13–20% overall yields. First use of intramolecular Mitsunobu cyclization for 1,2,3,4-
tetrahydroquinoxalines followed by PPh3/I2/imidazole mediated 6-exo-tet cyclization were the key
steps.
ring (either B or C) of the pyrazino[1,2-a]quinoxaline nucleus was
Introduction
constructed on the available precursor.
Nitrogen-containing benzo-fused tricycles such as pyrrolo[1,2-
We have been working on the synthesis and biology of
a]quinoxalines,1 imidazo[1,5-a]quinoxalines,2,3d imidazo[1,2-
S-amino acid-based chiral heterocycles and natural product like
a]quinoxalines,3 [1,2,4]triazolo[4,3-a]quinoxalines,3a,4,5 and 1H-
imidazo[4,5-b]quinoxalines,6 2,3,4,4a-tetrahydro-1H-pyrazino-
[1,2-a]quinoxalin-5-(6H)-ones7 have a wide range of biological
activities. Among these compounds, 2,3,4,4a,5,6-hexahydro-
1H-pyrazino[1,2-a]quinoxalines
1H-pyrazino[1,2-a]quinoxalin-5-(6H)-ones
molecules.11 In continuation of our program, we became interested
in synthesizing a series of enantiomerically pure substituted
2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines following
a new synthetic route based on amino acids. In our approach, both
B and C rings were constructed with diversification obtained from
different type of amino acids.
and
2,3,4,4a-tetrahydro-
are common
structural units that are found in a wide range of biologically
important and therapeutically useful agents. They are used
as serotonin 5-hydroxytryptamine7,8 (5-HT) receptor agonists.
They are known to exhibit 5-HT2C agonist binding along with
antihypertensive activity.9 3-Substituted 2,3,4,4a,5,6-hexahydro-
1H-pyrazino[1,2-a]quinoxalines10 exhibited no anorexigenic
or stimulant activity at 60 mg kg-1 i. p. dose. 5-HT2C receptor
agonists are useful for the treatment of disorders such as obsessive-
compulsive disorder, depression, anxiety, schizophrenia, obesity,
type II diabetes migraine, sleep and eating disorders.
Mainly two synthetic approaches are known for the con-
struction of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxa-
lines. In the first approach,10 condensation of quinoxaline-
2-aldehyde with benzylamine followed by reduction, ring
closure with diethyl oxalate, and LAH reduction are the key
steps. It suffers from several drawbacks, giving 2-benzylamino-
methyl-1,2,3,4-tetrahydroquinoxaline along with 2-methyl-
1,2,3,4-tetrahydroquinoxaline when condensation at large scale
was performed and the reduction was not stereospecific as
well. In the second approach, quinoxalone was prepared from
4-carbobenzyloxypiperazine-2-carboxylic acid7 and substituted
1-halo-2-nitrobenzene via reduction of an aromatic nitro
group followed by lactam formation. Finally, reduction of
quinoxalone with BH3·THF furnished 2,3,4,4a,5,6-hexahydro-
1H-pyrazino[1,2-a]quinoxalines. In both approaches, only one
Results and discussion
The retrosynthetic strategy for pyrazino[1,2-a]quinoxaline is de-
lineated in Scheme 1. We envisioned that the pyrazino[1,2-
a]quinoxaline nucleus can be constructed by PPh3/I2/imidazole-
mediated 6-exo-tet type cyclization from intermediate D,
which could be readily obtained by intermolecular Mitsunobu
cyclization12 of F with N-tosyl amino acids methyl ester followed
by intramolecular Mitsunobu cyclization of intermediate E. The
preparation of the intermediate F is outlined in Scheme 2. To
begin with, S-amino acids 2a–b were reacted with 1-fluoro-2-
nitrobenzene 1 in the presence of K2CO3 and dry DMF at 80 ◦C
to furnish 2-nitrobenzene-protected amino acid derivatives, which
were converted to their methyl esters 3a–b in the presence of SOCl2
and MeOH. In addition, it was experimented to know whether
any racemization of the amino acids occurred upon nucleophilic
aromatic substitution. The chiral HPLC of 3a and 3b revealed
that the nucleophilic aromatic substitution of amino acid on 2-
nitrofluorobenzene took place without any racemization (see the
ESI‡). We used reference compound {mixture of S-3b and its
Medicinal and Process Chemistry Division, Central Drug Research In-
stitute, Lucknow, 226001, UP, India. E-mail: gautam.panda@gmail.com,
gautam_panda@cdri.res.in; Fax: 91-522-2623405; Tel: 91-522-2612411-18,
Ext. 4385, 4469
† Dedicated to Dr C. M. Gupta on the completion of his 65th birthday
‡ Electronic supplementary information (ESI) available: NMR and HPLC
spectra. See DOI: 10.1039/c000029a
Scheme 1 Retrosyntetic analysis of pyrazino[1,2-a]quinoxalines
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Scheme 2 Syntheses of compounds 5a–b
Scheme 4 Syntheses of pyrazino[1,2-a]quinoxalines 17a, 18a–e
enantiomer R-3b} to check the condition that was suitable for the
separation of racemic compounds. Silylation of 3 was performed
under two different conditions. The secondary hydroxy of 4a (R =
CH3) was protected using TBDMSOTf, 2,6-lutidine in dry DCM
at -78 ◦C with 68% yield. The primary hydroxy of 4b (R = H) was
protected by treatment with TBDMSCl, imidazole in dry DCM
with 83% yield. LiBH4 reduction of 4a–b furnished alcohols 5a–b
in 80–90% yield. The synthesis of intermediate E was achieved
by treatment of 5a–b with different N-tosyl protected amino acid
methyl esters under Mitsunobu conditions to furnish 7a, 8a–e in
75–85% yield, Scheme 3.
Both tosyl groups of the final molecules 17a, 18a–e were
deprotected (Scheme 5) by using sodium naphthalenide14 in dry
THF with 60–70% yields (Table 1). All the final molecules were
characterized by 1D NMR, mass, elemental analysis and the
enantiomeric purity and overall yields are shown in Table 1.
Scheme 5 Deprotection of the tosyl groups (17a, 18a–e)
Table 1 Yield of the tosyl groups deprotection step
Entry Comp no. Yield in deprotection (%) Overall yield from 1 (%)
1
2
3
4
5
6
17a
18a
18b
18c
18d
18e
63
62
65
64
68
64
13
14
17
20
17
17
Scheme 3 Syntheses of compounds 11a, 12a–e
The tosyl derivatives of amino acids were synthesized in two
steps; first amino acids were converted to their methyl esters by
the treatment with SOCl2 and MeOH, followed by tosylation with
p-toluenesulfonyl chloride and triethylamine in the presence of dry
DCM in good yields.
In summary, we have reported a twelve step synthesis of sub-
stituted 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines
with 13–20% overall yield from naturally abundant S-amino acids
for the first time. Inter and intramolecular Mitsunobu cyclization,
and PPh3/I2/imidazole-mediated 6-exo-tet cyclization were the
key steps for the construction of the pyrazino[1,2-a]quinoxaline
nucleus. Each step was operationally simple and high yielding
conversion. Both the B and C ring were constructed with
diversification from amino acids unlike the reported procedure.7,10
Removal of the tosyl group with high yield is generally difficult.
We have removed both tosyl groups of all the final molecules 17a,
18a–e with 60–70% yield using sodium naphthalenide protocol.
Biological evaluations of this series are currently under way.
Desilylation of 7a in the presence of AcOH–THF–H2O (3 : 1 : 1)
at reflux for 12 h, and 8a–e by TBAF, gave alcohols 9a and 10a–e,
respectively, in good yields. It is noted that a successful Mitsunobu
displacement reaction is dependent on the pKa associated with
the incoming nucleophile and independent of the nucleophilicity
of the nucleophile.13 Hence, after reduction of the aromatic nitro
group by 10% Pd on activated charcoal, the amino functionality
was converted to its sulfonamide derivatives by treatment with
pyridine and tosyl chloride to afford 11a, 12a–e in good yields.
To achieve the target pyrazino[1,2-a]quinoxalines (Scheme 4),
11a, 12a–e were treated with DEAD/PPh3 under Mitsunobu
condition to furnish enantiomerically pure substituted 1,2,3,4-
tetrahydroquinoxalines in 75–85% yields. LiBH4 reduction of the
ester gave alcohols 15a, 16a–e, in 80–90% yields. The targeted
pyrazino[1,2-a]quinoxalines were obtained by PPh3/I2/imidazole-
mediated 6-exo-tet cyclization of 15a, 16a–e to provide 17a, 18a–e
in 75–85% yield.
Experimental
General methods
All chemicals were purchased from Aldrich Milwaukee, WI.
Melting points were determined on COMPLAB melting point
apparatus and are uncorrected. IR spectra were recorded on a
Perkin-Elmer FT-IR RXI spectrometer. 1H NMR and 13C NMR
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spectra were recorded on a Brucker DPX-200 or DPX-300 spec-
trometer using CDCl3 as solvent. Tetramethylsilane (0.00 ppm)
served as an internal standard in 1H NMR and CDCl3 (77.0 ppm)
in 13C NMR. Chemical shifts are expressed in parts per million
(ppm). Mass spectra were recorded on JEOL SX 102 spectrometer.
Elemental analyses were done on Varian EL-III C H N analyzer
(Germany). The enantiomeric excess was determined by Lichro-
CART Chiradex column (250 ¥ 4 mm, 5 mm) using water and
acetonitrile as eluent at 30 ◦C.
4.24 (m, 1H), 3.78-3.75 (m, 2H), 3.68-3.60 (m, 1H), 2.09 (bs, 1H),
1.23 (d, 3H, J = 6.3), 0.95 (s, 9H), 0.13-0.11 (m, 6H). 13C NMR
(75 MHz, CDCl3) 145.7, 136.1, 132.1, 127.0, 115.2, 114.1, 66.8,
62.5, 59.1, 25.7, 20.9, 17.9, -4.3, -5.1. MS (ESI): m/z 341 [M+H]+.
(R)-3-(tert-Butyldimethylsilyloxy)-2-(2-nitrophenylamino) pro-
pan-1-ol (5b). Same procedure as for 5a. Yellow oil. Yield, 87%;
Rf, 0.52 (7.0 : 3.0, hexane–ethyl acetate); IR (neat, cm-1): 3548,
3361, 2958, 1621, 1586, 1427, 771.1H NMR (300 MHz, CDCl3) d
8.42 (d, 1H, J = 7.8), 8.17 (dd, 1H, J1 = 1.4, J2 = 8.6), 7.44-7.38
(m, 1H), 6.93 (d, 1H, J = 8.7), 6.67-6.61 (m, 1H), 3.97-3.75 (m,
5H), 2.29 (bs, 1H), 0.93 (s, 9H), 0.10-0.09 (m, 6H). MS (ESI): m/z
327 [M+H].
Experimental procedures and characterization data of selected
examples
General experimental procedure for the synthesis of (3). To a
solution of 2a–b (1.2 eq) in 30 mL of DMF was added K2CO3
(3 equiv.) at 25 ◦C followed by ortho-nitro aryl fluorides (1 equiv.)
and was stirred for 4 h at 80 ◦C. K2CO3 was filtered off and DMF
was removed under vacuum. It was diluted with 30 mL MeOH
and followed by SOCl2 (2 equiv.) at 0 ◦C for 3–4 h. After removal
of solvent, it was diluted with water and added excess NaHCO3
to neutralize HCl and extracted with ethyl acetate. Removal of
solvent and column chromatography on silica gel with AcOEt–
hexane (1.5 : 8.5) as eluent furnished 3.
(S)-Methyl-2-(N -((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-
(2-nitrophenylamino)butyl)-4-methylphenylsulfonamido)-3-phenyl-
propanoate (7a). To a stirred solution of 5a (220 mg, 0.64 mmol),
6a (258 mg, 0.77 mmol) and triphenylphosphine (254 mg,
0.97 mmol) in THF (7 mL) was added DEAD (0.15 mL,
0.97 mmol) in THF drop wise at 0 ◦C and stirred for 2 h. It
◦
was allowed to warm to 25 C and was stirred for an additional
5 h. It was stirred with 1 : 1 mixture of hexane : diethylether;
triphenylphosphine oxide was filtered off. After usual work-up,
and concentration of solution, the chromatography (eluent =
hexane–ethyl acetate 8.5 : 1.5) of crude over silica gel furnished
7a (350 mg, 83%) as a yellow oil. Rf 0.51 (8.0 : 2.0, hexane–ethyl
acetate); IR (neat, cm-1): 3362, 2953, 1739, 1621, 1513, 1352, 1161,
(2S,3R)-Methyl-3-hydroxy-2-(2-nitrophenylamino)butanoate
(3a). Yellow oil; yield, 75% (two steps); Rf, 0.54 (6.5 : 3.5),
hexane–ethyl acetate); [a]3D0 = +121.7 (c 0.10, MeOH), HPLC
analysis: ee > 99 (tR = 5.5 min, CH3CN–H2O); IR (neat, cm-1):
3539, 3364, 2904, 1740, 1621, 1573, 1432, 742. 1H NMR (300 MHz,
CDCl3) d 8.57 (d, 1H, J = 7.9), 8.20 (dd, 1H, J1 = 1.4, J2 = 8.5),
7.47-7.41 (m, 1H), 6.79-6.70 (m, 2H), 4.42-4.40 (m, 1H), 4.21 (q,
1
763. H NMR (300 MHz, CDCl3) d 8.39 (d, 1H, J = 9.3), 8.18
(dd, 1H, J1 = 1.5, J2 = 8.6), 7.69-7.66 (m, 2H), 7.45-7.40 (m,
1H), 7.26-7.21 (m, 5H), 7.12-7.08 (m, 3H), 6.66-6.61 (m, 1H),
4.60-4.55 (m, 1H), 4.28-4.23 (m, 1H), 4.16-4.09 (m, 1H), 3.59 (dd,
1H, J1 = 6.1, J2 = 15.2), 3.43 (dd, 1H, J1 = 7.1, J2 = 15.2),
3.31-3.23 (m, 4H), 2.83-2.76 (m, 1H), 2.41 (s, 3H), 1.18 (d, 3H,
J = 6.2), 0.99 (s, 9H), 0.15-0.11 (m, 6H). 13C NMR (75 MHz,
CDCl3) 170.0, 145.6, 144.0, 136.15, 136.06, 135.9, 132.2, 129.6,
129.0, 128.6, 127.6, 127.0, 126.9, 115.2, 114.7, 67.7, 62.5, 58.0,
51.8, 48.1, 36.2, 25.9, 21.5, 20.9, 18.0, -3.5, -4.8. MS (ESI): m/z
656 [M+H]+. Anal. Calcd. (%) for C33H45N3O7SSi; C, 60.43; H,
6.92; N, 6.41; Found: C, 60.57; H, 6.98; N, 6.55.
1H, J = 3.1), 3.79 (s, 3H), 2.71 (bs, 1H), 1.35 (d, 3H, J = 6.4). 13
C
NMR (75 MHz, CDCl3) 171.6, 144.4, 136.2, 132.9, 127.0, 116.4,
113.8, 67.8, 61.0, 52.7, 19.9. MS (ESI): m/z 255 [M+H]+.
(2S,3R)-Methyl-3-(tert-butyldimethylsilyloxy)-2-(2-nitrophe-
nylamino)butanoate (4a). To a stirred solution of 3a (1 g,
3.93 mmol) in anhydrous DCM (15 mL) were added TBDMS-
OTf (0.82 ml, 4.72 mmol) and 2,6-lutidine (0.68 ml, 5.89 mmol) at
-78 ◦C and stirred for 12 h. It was diluted with water and extracted
with DCM. Removal of solvent and column chromatography on
silica gel with AcOEt–hexane (1.0 : 9.0) as eluent furnished 4a
(984 mg, 68%) as a yellow oil. Rf, 0.51 (9.5 : 0.5), hexane–ethyl
acetate); IR (neat, cm-1): 3368, 2957, 2367, 1742, 1627, 1579, 1434,
1151, 760.1H NMR (300 MHz, CDCl3) d 8.65 (d, 1H, J = 8.6),
8.22 (dd, 1H, J1 = 1.5, J2 = 8.5), 7.43-7.37 (m, 1H), 6.71-6.61 (m,
2H), 4.62-4.55 (m, 1H), 4.11-4.08 (m, 1H), 3.73 (s, 3H), 1.32 (d,
3H, J = 6.3), 0.92 (s, 9H), 0.12-0.03 (m, 6H). MS (ESI): m/z 369
[M+H]+.
General experimental procedure for the synthesis of 8
Same procedure as for 7a.
(S)-Methyl-2-(N-((R)-3-(tert-butyldimethylsilyloxy)-2-(2-nitro-
phenylamino)propyl) - 4 - methylphenylsulfonamido) - 3 - phenylpro -
panoate 8a. Yellow oil. Yield, 77%; Rf, 0.52 (9.0 : 1.0, hexane–
ethyl acetate); IR (neat, cm-1): 3366, 2954, 1742, 1616, 1509, 1342,
1158, 761. 1H NMR (300 MHz, CDCl3) d 8.32 (d, 1H, J = 8.7),
8.16 (dd, 1H, J1 = 1.5, J2 = 8.6), 7.65-7.63 (m, 2H), 7.49-7.45 (m,
1H), 7.26-7.13 (m, 8H), 6.67-6.63 (m, 1H), 4.63 (dd, 1H, J1 = 1.8,
J2 = 9.6, 4.25 (bs, 1H), 4.09 (dd, 1H, J1 = 1.8, J2 = 10.5), 3.73
(dd, 1H, J1 = 3.3, J2 = 10.5), 3.57 (dd, 1H, J1 = 9.4, J2 = 15.4),
3.32-3.28 (m, 2H), 3.23 (s, 3H), 3.01 (dd, 1H, J1 = 5.8, J2 = 13.6),
2.38 (s, 3H), 0.93 (s, 9H), 0.11-0.03 (m, 6H). 13C NMR (75 MHz,
CDCl3) d 170.3, 144.4, 144.0, 136.3, 136.1, 135.2, 132.2, 129.5,
129.1, 128.6, 127.8, 127.1, 127.0, 115.6, 114.5, 62.5, 60.9, 53.2,
51.7, 45.5, 37.2, 25.9, 21.5, 18.2, -5.5, -5.6. MS (ESI): m/z 642
[M+H], 664 [M+Na]+. Anal. Calcd. (%) for C32H43N3O7SSi; C,
59.88; H, 6.75; N, 6.55; Found: C, 59.92; H, 6.79; N, 6.69.
(2R,3R)-3-(tert-Butyldimethylsilyloxy)-2-(2-nitrophenylamino)-
butan-1-ol (5a). To a stirred solution of 4a (650 mg, 1.76 mmol)
in anhydrous THF (10 mL) was added a solution of LiBH4 (2M)
(1.05 mL, 2.11 mmol) at 0 ◦C. It was stirred at RT for 3 h and
was quenched by ethyl acetate followed by water at 0 ◦C. After
usual work-up, the crude was chromatographed on silica gel with
hexane–ethyl acetate, 8.5 : 1.5 as eluent to furnish 5a (510 mg, 85%)
as a yellow oil. Rf 0.51 (AcOEt–hexane, 2.5 : 7.5); IR (Neat, cm-1):
1
3543, 3364, 2951, 1622, 1584, 1421, 788. H NMR (300 MHz,
CDCl3) d 8.49 (d, 1H, J = 8.4), 8.18 (dd, 1H, J1 = 1.5, J2 = 8.6),
7.43-7.37 (m, 1H), 6.97 (d, 1H, J = 8.6), 6.65-6.60 (m, 1H), 4.31-
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(S)-Methyl 2-(N-((R)-3-(tert-butyldimethylsilyloxy)-2-(2-nitro-
phenylamino)propyl)-4-methylphenylsulfonamido)propanoate 8b.
Yellow oil. Yield, 80%; Rf, 0.51 (8.5 : 1.5, hexane–ethyl acetate);
IR (neat, cm-1): 3361, 2959, 1739, 1616, 1510, 1153, 760. 1H
NMR (300 MHz, CDCl3 + CCl4) d 8.36 (d, 1H, J = 8.6), 8.19
(dd, 1H, J1 = 1.3, J2 = 8.6), 7.67-7.65 (m, 2H), 7.54-7.50 (m,
1H), 7.34-7.24 (m, 3H), 6.70-6.65 (m, 1H), 4.60 (q, 1H, J = 7.3),
4.32-4.30 (m, 1H), 4.12-4.09 (m, 1H), 3.78 (dd, 1H, J1 = 3.0, J2 =
10.4), 3.38 (s, 3H), 3.31-3.29 (m, 2H), 2.42 (s, 3H), 1.52 (d, 3H,
J = 7.3), 0.95 (s, 9H), 0.15-0.10 (m, 6H). 13C NMR (75 MHz,
CDCl3) d 171.1, 144.4, 143.6, 136.2, 135.5, 132.3, 129.5, 127.7,
127.1, 115.5, 114.6, 60.6, 56.6, 53.1, 51.9, 44.8, 26.0, 21.6, 18.3,
16.9, -5.4. MS (ESI): m/z 566 [M+H], 588 [M+Na]+. Anal. Calcd.
(%) for C26H39N3O7SSi; C, 55.20; H, 6.95; N, 7.43; Found: C,
55.29; H, 7.01; N, 7.56.
General experimental procedure for the synthesis of 12
To a stirred solution of 8 (1 equiv.) in THF (20 mL) under N2, was
◦
added TBAF (1 M) (1.2 equiv.) at 0 C and was stirred for 1 h.
After removal of solvent and usual work-up, the crude was directly
dissolved in MeOH and added Pd (10% on carbon) and was under
pressure of 50 psi of H2 for 1.3 h. After filtration through Celite
and removal of solvent, crude was dissolved in 10 mL anhydrous
pyridine at 0 ◦C, followed by addition of p- toluenesulfonylchloride
(1.1 equiv.). and kept in the refrigerator for 12 h. Removal of
pyridine and usual work-up and chromatography afforded the
title compound 12.
(S)-Methyl-2-(N-((R)-3-hydroxy-2-(2-(4-methylphenylsulfon-
amido)phenylamino)propyl)-4-methylphenylsulfonamido)-3-phe-
nylpropanoate 12a. Light brown oil. Yield, 46% (in three steps);
Rf 0.51 (9.8 : 0.2, CHCl3–MeOH). IR (neat, cm-1): 3519, 3398,
3262, 1737, 1159, 761. 1H NMR (300 MHz, CDCl3) d 7.67-7.59 (m,
5H), 7.49-7.44 (m, 1H), 7.25-7.17 (m, 8H), 7.10-7.07 (m, 3H), 6.66-
6.62 (m, 1H), 6.50-6.45 (m, 1H), 4.99-4.90 (m, 1H), 4.76-4.70 (m,
1H), 4.23-4.15 (m, 1H), 3.78-3.71 (m, 2H), 3.64-3.63 (m, 1H), 3.43
(s, 3H), 3.28 (dd, 1H, J1 = 8.4, J2 = 13.8), 2.86 (dd, 1H, J1 = 6.7,
J2 = 14.0), 2.41 (s, 3H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3) d
171.3, 144.1, 143.8, 136.4, 136.3, 136.2, 132.2, 132.0, 129.6, 129.5,
129.0, 128.65, 128.59, 127.7, 127.4, 126.9, 121.1, 117.0, 112.2, 61.7,
60.4, 53.4, 52.3, 46.0, 36.0, 21.6, 21.1. MS (ESI): m/z 652[M+H]+.
(%) Anal. Calcd. for C33H37N3O7S2; C, 60.81; H, 5.72; N, 6.45;
Found: C, 60.90; H, 5.79; N, 6.51.
(S)-Methyl-2-(N-((2R,3R)-3-hydroxy-2-(2-nitrophenylamino)-
butyl)-4-methylphenylsulfonamido)-3-phenylpropanoate 9a. To a
solution of 7a (350 mg) in 10 mL AcOH–THF–H2O (3 : 1 : 1,
v/v/v) was refluxed at 120 ◦C for 16 h. It was extracted with
EtOAc. The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to afford a yellow oil that was purified
by column chromatography on silica gel with AcOEt–hexane
(2.5 : 7.5) as eluent to furnish 9a (245 mg, 85%) as a yellow oil. Rf,
0.51 (7.0 : 3.0, hexane–ethyl acetate); IR (neat, cm-1): 3660, 3361,
1740, 1617, 1509, 1219, 760. 1H NMR (300 MHz, CDCl3) d 8.39 (d,
1H, J = 8.9), 8.19 (dd, 1H, J1 = 1.4, J2 = 8.6), 7.66-7.62 (m, 2H),
7.53-7.45 (m, 1H), 7.28-7.20 (m, 5H), 7.09-7.02 (m, 3H), 6.69-6.62
(m, 1H), 4.73-4.65 (m, 1H), 4.34-4.33 (m, 1H), 4.00-3.89 (m, 1H),
3.48 (s, 3H), 3.32-3.21 (m, 2H), 2.80-2.70 (m, 2H), 2.41 (s, 3H),
1.21 (d, 3H, J = 6.4). 13C NMR (75 MHz, CDCl3) d 171.1, 145.2,
144.2, 136.4, 135.8, 135.6, 132.4, 129.8, 128.8, 128.7, 127.4, 127.2,
127.0, 115.4, 113.9, 63.7, 61.2, 55.9, 52.3, 45.6, 35.4, 21.5, 20.0.
MS (ESI): m/z 542 [M+H]+. Anal. Calcd. (%) for C27H31N3O7S;
C, 59.87; H, 5.77; N, 7.76; Found: C, 59.88; H, 5.81; N, 7.89.
(S)-Methyl-2-(N-((R)-3-hydroxy-2-(2-(4-methylphenylsulfon-
amido)phenylamino)propyl)-4-methylphenylsulfonamido)propano-
ate 12b. Same procedure as for 12a. Brown oil. Yield, 45% (in
three steps); Rf 0.48 (9.8 : 0.2, CHCl3–MeOH). IR (neat, cm-1):
1
3524, 3405, 3025, 1741, 1331, 1159, 765. H NMR (300 MHz,
CDCl3) d 7.66-7.63 (m, 4H), 7.24-7.18 (m, 4H), 7.08-7.03 (m, 1H),
6.85 (bs, 1H), 6.65-6.60 (m, 2H), 6.48-6.43 (m, 1H), 4.99-4.98 (bs,
1H), 4.64 (q, 1H, J = 7.4), 3.79-3.68 (m, 2H), 3.55 (s, 3H), 3.42-
3.24 (m, 2H), 2.74 (bs, 1H), 2.41 (s, 3H), 2.38 (s, 3H), 1.38 (d,
3H, J = 7.2). 13C NMR (75 MHz, CDCl3) d 172.3, 144.2, 143.5,
143.4, 136.7, 136.6, 129.6, 129.5, 129.4, 129.0, 128.8, 127.8, 127.3,
121.1, 116.8, 112.0, 60.6, 55.9, 53.4, 52.4, 45.5, 21.63, 21.60, 15.9.
MS (ESI): m/z 576 [M+H], 598 [M+Na]+. (%)Anal. Calcd. for
C27H33N3O7S2; C, 56.33; H, 5.78; N, 7.30; Found: C, 56.44; H,
5.87; N, 6.92.
(S)-Methyl-2-(N-((2R,3R)-3-hydroxy-2-(2-(4-methylphenylsul-
fonamido)phenylamino)butyl)-4-methylphenylsulfonamido)-3-phe-
nylpropanoate (11a). To a solution of 9a (350 mg, 0.64 mmol) in
MeOH was added Pd (10% on carbon) and was allowed to run
for 1 h under pressure of 50 psi of H2. After usual work up, the
crude (220 mg, 0.43 mmol) was dissolved in 5 mL anhydrous pyri-
dine, followed by addition of p- toluenesulfonylchloride (82 mg,
0.43 mmol) and kept in refrigerator for 12 h. The pyridine was
removed and usual work up and chromatography on silica gel with
eluent EtOAc–hexane (3.5 : 6.5) to afford 11a (198 mg, 46% in two
steps) as a light brown oil. Rf, 0.48 (5.5 : 4.5, hexane–ethylacetate);
IR (neat, cm-1): 3516, 3401, 3022, 2928, 1738, 1328, 1154, 753. 1H
NMR (300 MHz, CDCl3) d 7.71-7.68 (m, 2H), 7.63-7.60 (m, 2H),
7.27-7.18 (m, 7H), 7.08-7.03 (m, 3H), 6.78-6.66 (m, 3H), 6.48-6.43
(m, 1H), 4.89-4.86 (m, 1H), 4.67-4.62 (m, 1H), 4.09-4.07 (m, 1H),
3.69-3.67 (m, 1H), 3.53-3.45 (m, 1H), 3.42 (s, 3H), 3.30-3.21 (m,
2H), 2.86 (bs, 1H), 2.76 (dd, 1H, J1 = 6.2, J2 = 13.7), 2.42 (s, 3H),
2.40 (s, 3H), 1.14 (d, 3H, J = 6.4). 13C NMR (75 MHz, CDCl3) d
171.0, 145.2, 143.8, 143.6, 136.5, 136.2, 135.9, 129.6, 129.5, 129.24,
129.19, 128.9, 128.5, 127.6, 127.5, 127.3, 126.8, 120.2, 116.1, 111.4,
65.7, 61.4, 60.3, 56.0, 52.1, 46.3, 21.5, 21.4, 19.8. MS (ESI): m/z
666 [M+H]+. Anal. Calcd. (%) for C34H39N3O7S2; C, 61.33; H,
5.90; N, 6.31; Found: C, 61.47; H, 5.98; N, 6.43.
(S)-Methyl-2-(4-methyl-N-(((2R,3S)-3-methyl-4-tosyl-1,2,3,4-
tetrahydroquinoxalin-2-yl)methyl)phenylsulfonamido)-3-phenyl-
propanoate 13a. To a stirred solution of 11a (180 mg, 0.27 mmol),
and triphenylphosphine (85 mg, 0.32 mmol) in anhydrous THF
(7 mL) under N2, was added DEAD (0.05 mL, 0.32 mmol)
in THF drop wise at 0 ◦C and stirred for 2 h. Removal of
triphenylphosphine oxide and usual procedure furnished 13a
144 mg, 82%) as a colorless oil. Rf 0.51 (7.5 : 2.5, hexane–ethyl
acetate). IR (neat, cm-1): 3392, 3020, 2358, 1739, 1159, 761. H
1
NMR (300 MHz, CDCl3 + CCl4) d 7.78-7.75 (m, 2H), 7.66-7.64
(m, 2H), 7.27-7.18 (m, 10H), 6.93-6.90 (m, 2H), 6.67-6.63 (m, 1H),
4.86-4.81 (m, 1H), 4.36-4.29 (m, 2H), 3.51-3.46 (m, 1H), 3.37 (s,
3H), 3.27 (dd, 1H, J1 = 8.4, J2 = 13.9), 2.91 (dd, 1H, J1 = 7.1,
J2 = 13.9), 2.60-2.54 (m, 1H), 2.40 (s, 3H), 1.40 (d, 3H, J = 5.8).
13C NMR (75 MHz, CDCl3 + CCl4) d 170.8, 143.5, 137.4, 136.8,
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136.1, 131.4, 129.5, 129.1, 128.7, 127.6, 127.3, 127.0, 124.8, 123.7,
119.7, 119.1, 61.2, 52.0, 43.5, 43.5, 43.4, 41.9, 36.6, 21.6, 14.5. MS
(ESI): m/z 648 [M+H]+. Anal. Calcd. (%) for C34H37N3O6S2; C,
63.04; H, 5.76; N, 6.49; Found: C, 63.24; H, 5.98; N, 6.43.
1H), 3.98-3.91 (m, 1H), 3.55-3.50 (m, 2H), 3.39-3.33 (m, 2H), 3.30-
3.21 (m, 1H), 2.99-2.91 (m, 1H), 2.46-2.43 (m, 4H), 2.35 (s, 3H).
MS (ESI): m/z 606 [M+H]+. Anal. Calcd. (%) for C32H35N3O5S2;
C, 63.45; H, 5.82; N, 6.94. Found: C, 63.59; H, 5.94; N, 7.10.
(S)-Methyl-2-(4-methyl-N-(((R)-4-tosyl-1,2,3,4-tetrahydroqui-
noxalin-2-yl)methyl)phenylsulfonamido)-3-phenylpropanoate 14a.
Same procedure as for 13a Colorless oil. Yield, 79%; Rf 0.50
(7.5 : 2.5, hexane–ethyl acetate). IR (neat, cm-1): 3382, 3022, 2362,
1736, 1217, 768. 1H NMR (300 MHz, CDCl3) d 7.57-7.55 (m, 2H),
7.49-7.44 (m, 2H), 7.28-7.23 (m, 5H), 7.15-7.13 (m, 2H), 7.09-7.05
(m, 2H), 6.99-6.94 (m, 1H), 6.70-6.64 (m, 1H), 6.43 (dd, 1H, J1 =
1.2, J2 = 8.0), 4.85 (bs, 1H), 4.60 (dd, 1H, J1 = 6.4, J2 = 9.0),
4.17-4.12 (m, 1H), 3.42 (s, 3H), 3.29-3.20 (m, 1H), 3.11-3.07 (m,
2H), 3.02-2.95 (m, 2H), 2.70 (dd, 1H, J1 = 6.4, J2 = 13.54, 2.43
(s, 3H), 2.23 (s, 3H). 13C NMR (75 MHz, CDCl3) d 170.6, 144.1,
143.8, 137.2, 136.2, 135.6, 135.5, 129.7, 129.6, 129.0, 128.8, 128.71,
128.67, 127.5, 127.2, 126.5, 125.4, 121.3, 117.0, 114.8, 61.6, 52.1,
48.8, 47.6, 46.7, 37.6, 21.5, 21.3. MS (ESI): m/z 634 [M+H]+. Anal.
Calcd.(%) for C33H35N3O6S2; C, 62.54; H, 5.57; N, 6.63. Found: C,
62.65; H, 5.66; N, 6.52.
N-((S)-1-Hydroxypropan-2-yl)-4-methyl-N-(((R)-4-tosyl-1,2,3,
4-tetrahydroquinoxalin-2-yl)methyl)benzenesulfon amide 16b.
Same procedure like for 5. Colorless oil. yield, 81%; Rf 0.51
(6.0 : 4.0, hexane–ethylacetate). IR (neat, cm-1): 3522, 3396, 2959,
1499, 1161, 761.1H NMR (300 MHz, CDCl3) d 7.66-7.64 (m, 2H),
7.56-7.45 (m, 3H), 7.31-7.19 (m, 4H), 6.98-6.88 (m, 1H), 6.69-6.59
(m, 1H), 6.51 (d, 1H J = 8.1), 4.19-4.06 (m, 2H), 3.97-3.90 (m,
1H), 3.49-3.43 (m, 1H), 3.29-3.20 (m, 2H), 3.03-3.01 (m, 1H), 2.69
(dd, 1H, J1 = 10.0, J2 = 14.6), 2.45 (s, 3H), 2.37 (s, 3H), 0.66 (d,
3H, J = 6.8). 13C NMR (75 MHz, CDCl3) d 143.6, 137.2, 136.8,
129.9, 129.83, 129.77, 127.4, 127.3, 127.2, 126.6, 126.3, 125.4,
124.4, 117.3, 115.4, 115.3, 63.7, 55.9, 51.0, 48.2, 46.9, 21.6, 13.4.
MS (ESI): m/z 530 [M+H]+. Anal. Calcd. (%) for C26H31N3O5S2;
C, 58.96; H, 5.90; N, 7.93. Found: C, 58.91; H, 5.98; N, 7.78.
(2S,4aR,5S)-2-Benzyl-5-methyl-3,6-ditosyl-2,3,4,4a,5,6-hexa-
hydro-1H-pyrazino[1,2-a]quinoxaline 17a. A stirred solution of
15a (120 mg, 0.19 mmol), triphenylphosphine (76 mg, 0.29 mmol),
imidazole (39 mg, 0.57 mmol) and iodine (73 mg, 0.29 mmol) in
anhydrous toluene (7 mL) at 40 ◦C was stirred. After 20 min, 10%
aqueous Na2S2O3 (20 mL) was added and stirring was continued
for another 10 min and was extracted with EtOAc. After usual
work up and column chromatography (eluent = hexane–ethyl
acetate, 9.0 : 1.0) afforded 17a (90 mg, 78%) as a colorless oil.
(S)-Methyl-3-methyl-2-(4-methyl-N-(((R)-4-tosyl-1,2,3,4-tetra-
hydroquinoxalin-2-yl)methyl)phenylsulfonamido)butanoate
14c.
Same procedure as for 13a. Colorless oil. Yield, 84%; Rf 0.45
(7.5 : 2.5, hexane–ethyl acetate). IR (neat, cm-1): 3396, 3022, 2956,
1
1738, 1156, 761. H NMR (300 MHz, CDCl3) d 7.66-7.58 (m,
3H), 7.48-7.45 (m, 2H), 7.27-7.19 (m, 4H), 6.99-6.93 (m, 1H),
6.68-6.63 (m, 1H), 6.48 (dd, 1H, J1 = 1.0, J2 = 8.0), 5.00 (bs, 1H),
4.36-4.29 (m, 1H), 4.21-4.16 (m, 1H), 4.04-4.00 (m, 1H), 3.51-3.46
(m, 1H), 3.42 (s, 3H), 3.07-2.86 (m, 2H), 2.43 (s, 3H), 2.40 (s,
3H), 1.80-1.72 (m, 1H), 0.89 (d, 3H, J = 6.5), 0.82 (d, 3H, J =
6.5). 13C NMR (75 MHz, CDCl3) d 170.7, 143.7, 143.2, 137.5,
136.9, 136.0, 129.6, 129.5, 127.7, 127.4, 126.6, 125.6, 121.4, 117.0,
114.9, 64.1, 51.5, 48.3, 48.2, 46.9, 29.3, 21.65, 21.58, 19.8, 19.5,
MS (ESI): m/z 586 [M+H]+. Anal. Calcd. (%) for C29H35N3O6S2;
C, 59.47; H, 6.02; N, 7.17. Found: C, 59.58; H, 6.10; N, 7.26.
[a]3D0 = +151.8 (c 0.11, MeOH), HPLC analysis: ee > 99 (tR
=
13.5 min, CH3CN–H2O); IR (neat, cm-1): 3454, 2925, 1607, 1348,
1159, 761. 1H NMR (300 MHz, CDCl3) d 7.77 (d, 1H, J = 8.2),
7.66-7.58 (m, 2H), 7.34-7.24 (m, 9H), 7.17-7.10 (m, 3H), 7.01-6.92
(m, 2H), 4.33-4.32 (m, 1H), 4.22-4.10 (m, 1H), 3.96-3.93 (m, 1H),
3.50-3.41 (m, 1H), 3.30-3.27 (m, 1H), 3.11-3.04 (m, 2H), 2.98-2.90
(m, 1H), 2.71-2.66 (m, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 1.52 (d, 3H,
J = 7.2). 13C NMR (75 MHz, CDCl3) d 144.2, 143.5, 137.2, 137.1,
136.8, 136.6, 134.1, 129.75, 129.68, 129.1, 128.7, 127.3, 127.2,
127.1, 127.05, 127.03, 126.7, 123.8, 123.2, 119.1, 63.0, 56.7, 54.2,
50.2, 42.5, 36.1, 21.4, 14.0. MS (ESI): m/z 602 [M+H]+. Anal.
Calcd. (%) for C33H35N3O4S2; C, 65.86; H, 5.86; N, 6.98 ;Found:
C, 65.66; H, 5.75; N, 7.17.
N -((S)-1-Hydroxy-3-phenylpropan-2-yl)-4-methyl-N -(((2R,
3S)-3-methyl-4-tosyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methyl)-
benzenesulfonamide 15a. Same procedure as for 5. Colorless
oil. Yield, 83%; Rf 0.52 (6.0 : 4.0, hexane–ethyl acetate). IR
(neat, cm-1): 3534, 3401, 2959, 1498, 1159, 761. 1H NMR
(300 MHz, CDCl3 + CCl4) d 7.80-7.74 (m, 3H), 7.35-7.32 (m, 2H),
7.26-7.13 (m, 8H), 7.06-7.01 (m, 2H), 6.97-6.93 (m, 2H), 4.14-4.07
(m, 2H), 3.91-3.77 (m, 2H), 3.62-3.58 (m, 1H), 3.39-3.18 (m, 3H),
3.02-2.91 (m, 1H), 2.45 (s, 3H), 2.40 (s, 3H), 1.55 (d, 3H, J = 5.9).
13C NMR (75 MHz, CDCl3 + CCl4) d 143.6, 137.6, 137.5, 137.2,
130.7, 129.9, 129.6, 129.2, 128.6, 127.4, 127.2, 126.5, 125.9, 124.4,
121.2, 120.6, 62.1, 61.2, 46.0, 43.1, 42.7, 33.5, 21.6, 14.5. MS (ESI):
m/z 620 [M+H]+. Anal. Calcd. (%) for C33H37N3O5S2; C, 63.95;
H, 6.02; N, 6.78;. Found: C, 63.79; H, 6.18; N, 7.61.
(2S,4aR)-2-Benzyl-3,6-ditosyl-2,3,4,4a,5,6-hexahydro-1H-pyr-
azino[1,2-a]quinoxaline 18a. Same procedure as for 17a. Color-
less oil. Yield, 83%; [a]3D0 = -30.4 (c 0.13, MeOH), HPLC analysis:
ee > 99 (tR = 14.8 min, CH3CN–H2O); Rf 0.45 (9.0 : 1.0, hexane–
ethyl acetate). IR (neat, cm-1): 3456, 2925, 1606, 1342, 1162, 756.
1H NMR (300 MHz, CDCl3) d 7.60-7.58 (m, 3H), 7.37-7.35 (m,
2H), 7.30-7.26 (m, 5H), 7.16-7.14 (m, 2H), 7.07-7.04 (m, 3H), 6.82-
6.79 (m, 1H), 6.45 (d, 1H, J = 7.9), 4.20-4.12 (m, 2H), 3.55 (dd, 1H,
J1 = 2.6, J2 = 12.7), 3.40-3.28 (m, 2H), 2.80-2.70 (m, 2H), 2.58-2.52
(m, 2H), 2.46 (s, 3H), 2.34 (s, 3H), 2.24-2.18 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 143.7, 143.3, 140.1, 137.75, 137.69, 136.2,
129.9, 129.8, 129.5, 129.3, 128.8, 128.7, 127.4, 127.25, 127.20,
127.0, 126.8, 125.0, 118.8, 113.1, 54.9, 52.1, 47.8, 46.9, 43.5, 34.5,
21.6, 21.5. MS (ESI): m/z 588 [M+H]+, 610 [M+Na]+. Anal. Calcd.
(%) for C32H33N3O4S2; C, 65.39; H, 5.66; N, 7.15; Found: C, 65.51;
H, 5.75; N, 7.10.
N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-4-methyl-N-(((R)-4-
tosyl - 1,2,3,4 - tetrahydroquinoxalin - 2 - yl)methyl)benzene sulfon -
amide 16a. Same procedure as for 5. Colorless oil. Yield, 84%; Rf
0.53 (6.0 : 4.0, hexane–ethyl acetate). IR (neat, cm-1): 3525, 3398,
1
2958, 1498, 1160, 771. H NMR (300 MHz, CDCl3) d 7.63-7.53
(m, 5H), 7.30-7.21 (m, 7H), 6.99-6.95 (m, 3H), 6.70-6.64 (m, 1H),
6.50 (dd, 1H, J1 = 1.0, J2 = 8.1), 4.25-4.18 (m, 1H), 4.15-4.10 (m,
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(2S,4aR)-2-Methyl-3,6-ditosyl-2,3,4,4a,5,6-hexahydro-1H-pyr-
azino[1,2-a]quinoxaline 18b. Same procedure like for 17a. Col-
orless oil. Yield, 80%; [a]3D0 = +171.5 (c 0.10, MeOH), HPLC
analysis: ee > 99 (tR = 9.6 min, CH3CN–H2O); Rf 0.51 (7.5 : 2.5,
hexane–ethylacetate). IR (neat, cm-1): 3461, 3024, 2927, 1600,
Acknowledgements
This research project was supported by Department of Science and
Technology, New Delhi, India. Krishnananda thanks CSIR for
providing fellowship (NET-SRF). This has CDRI communication
no. 7885.
1
1344, 1162, 759. H NMR (300 MHz, CDCl3) d 7.65-7.62 (m,
2H), 7.55 (dd, 1H, J1 = 1.3, J2 = 8.1), 7.38-7.29 (m, 4H), 7.19-
7.15 (m, 2H), 7.07-7.01 (m, 1H), 6.76-6.71 (m, 1H), 6.57 (d, 1H,
J = 8.1), 4.20-4.08 (m, 2H), 3.55-3.52 (m, 1H), 3.38-3.34 (m, 1H),
3.19 (dd, 1H, J1 = 9.5, J2 = 14.1), 3.09-3.00 (m, 1H), 2.62-2.58
(m, 2H), 2.46 (s, 3H), 2.39 (s, 3H), 0.96 (d, 3H, J = 6.6). 13C
NMR (75 MHz, CDCl3) d 143.6, 143.2, 140.1, 137.7, 136.3, 129.7,
129.4, 127.4, 127.2, 127.1, 126.9, 124.8, 118.4, 112.8, 52.2, 51.5,
48.7, 47.0, 42.7, 21.6, 21.5, 14.3. MS (ESI): m/z 512 [M+H]+, 534
[M+Na]+. Anal. Calcd. (%) for C26H29N3O4S2; C, 61.03; H, 5.71;
N, 8.21; Found: C, 61.27; H, 5.79; N, 8.35.
Notes and references
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C. Fracasso, S. Caccia and T. Mennini, J. Med. Chem., 1999, 42, 4362;
(b) J. Guillon, P. Grellier, M. Labaied, P. Sonnet, M. J. Legˆer, R. De’prez-
Poulain, I. Forfar-Bares, P. Dallemagne, N. Lemaˆıtre, F. Pe’hourcq, J.
Rochette, C. Sergheraert and C. Jarry, J. Med. Chem., 2004, 47, 1997.
2 M. S. G. Sundaram, B. Singh, C. Venkatesh, H. Ila and H. Junjappa,
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3 (a) J. Ohmori, M. Shimizu-Sasamata, M. Okada and S. Sakamoto,
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C. Deleuze-Masque’fa, V. Benezech, J.-R. Fabreguettes, J.-P. Vidal, T.
Pocock, K. Elliott, R. Small, R. Escale, A. Michel, J.-P. Chapat and
P.-A. Bonnet, Eur. J. Med. Chem., 2001, 36, 255; (c) C. Deleuze-
Masque’fa, G. Gerebtzoff, G. Subra, J.-R. Fabreguettes, A. Ovens, M.
Carraz, M.-P. Strub, J. Bompart, P. George and P.-A. Bonnet, Bioorg.
Med. Chem., 2004, 12, 1129; (d) G. Moarbess, C. Deleuze-Masquefa,
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General experimental procedure for the synthesis of 19, 20a–
e. Sodium metal (20 equiv.) and naphthalene (22 equiv.) were
dissolved in 10 mL dry THF and stirred for 2 h, until a dark green
colour appeared. The desired THF solution of 17a, 18a–e (1 equiv.)
was cooled to -78 ◦C and then Na–napthalenide solution was
added dropwise via a syringe, unt◦il a dark green colour persisted
and stirred for 10–20 min at -78 C. It was quenched by adding
1–2 drops water and usual work up followed by chromatography
(eluent = methanol–chloroform 1.0 : 9.0) of crude over silica gel
furnished 19, 20a–e in 60–70% yield.
4 R. Sarges, H. R. Howard, R. G. Browne, L. A. Lebel, P. A. Seymour
and B. K. Koe, J. Med. Chem., 1990, 33, 2240.
5 (a) A. Unciti-Broceta, J. Pineda-de-las-Infantas, J. J. Diaz-Mocho’n,
R. Romagnoli, P. G. Baraldi, M. A. Gallo and A. Espinosa, J. Org.
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7 S. S. Welmaker, A. J. Nelson, E. J. Sabalski, L. A. Sabb, R. J. Potoski,
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(2S,4aR,5S)-2-Benzyl-5-methyl-2,3,4,4a,5,6-hexahydro-1H -
pyrazino[1,2-a]quinoxaline (19). Light brown oil. Yield, 63%; Rf,
0.52 (8.8 : 1.2, chloroform–methanol); IR (neat, cm-1): 3447, 3022,
1
2362, 1649, 1216, 765. H NMR (300 MHz, CDCl3) d 7.24-7.16
(m, 5H), 6.81-6.78 (m, 4H), 3.59-3.56 (m, 1H), 3.32 (bs, 1H), 3.17-
3.14 (m, 2H), 3.05-3.01 (m, 3H), 2.91-2.83 (m, 2H), 1.38 (d, 3H,
J = 6.7). 13C NMR (75 MHz, CDCl3) d 136.3, 136.1, 129.3, 129.1,
128.4, 128.3, 126.2, 118.65, 118.56, 115.6, 115.4, 61.3, 60.4, 58.6,
43.8, 37.3, 14.5. MS (ESI): m/z 204 [M+H]+, Anal. Calcd. (%) for
C12H17N3; C, 70.90; H, 8.43; N, 20.67; Found: C, 70.96; H, 8.51;
N, 20.61.
8 A. L. Sabb,; G. S. Welmaker,; J. A. Nelson, U.S. Pat. Nos. 7098338,
August 29, 2006.
9 (a) J. R. Potoski, US Pat., No. 4032639; June 28, 1977; (b) J. R. Potoski,
US Pat., No. 4089958; May 16, 1978 .
10 N. Kumar, P. C. Jain and N. Anand, Indian J. Chem., 1979, 17B, 244.
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Panda, Tetrahedron Lett., 2009, 50, 4703; (i) S. K. Das, A. K. Srivastava
and G. Panda, Tetrahedron Lett., 2010, 51, 1483.
12 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) K. C. Kumara Swamy, N. N.
Bhuvan Kumar, E. Balaraman and K. V. P. Pavan Kumar, Chem. Rev.,
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13 I. Koppel, J. Kippel, F. Degerbeck, L. Grehn and V. Ragnarsson, J. Org.
Chem., 1991, 56, 7172.
14 S. C. Bergmeier and P. P. Seth, Tetrahedron Lett., 1999, 40, 6181.
(2S,4aR)-2-Benzyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]-
quinoxaline (20a). Light brown oil. Yield, 62%; Rf, 0.51 (9.0 : 1.0,
chloroform–methanol); IR (neat, cm-1): 3022, 2364, 1216, 766.
1H NMR (300 MHz, CDCl3) d 7.34-7.22 (m, 5H), 6.68 (s, 3H),
6.55-6.53 (m, 1H), 3.51-3.39 (m, 3H), 3.29-3.18 (m, 2H), 3.04-
2.94 (m, 5H). 13C NMR (75 MHz, CDCl3) d 138.9, 135.5, 129.3,
128.7, 126.5, 120.0, 118.7, 114.6, 114.2, 54.5, 53.6, 43.8, 36.8.
MS (ESI): m/z 280 [M+H]+, Anal. Calcd. (%) for C18H21N3;
C, 77.38; H, 7.58; N, 15.04; Found: C, 77.34; H, 7.51; N,
15.11.
2828 | Org. Biomol. Chem., 2010, 8, 2823–2828
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