A Convenient Synthesis of Octahydro-pyrazino[1,2-a]pyrazine

Article abstract of DOI:10.1081/SCC-120028357

Octahydro-pyrazino[1,2-a]pyrazine has been prepared by a new and efficient method starting from 1,3-dichloro-2-propanol and N-tosylated diethylenetriamine. The structure of title compound was determined by spectroscopy and x-ray diffraction technique.

Full text of DOI:10.1081/SCC-120028357

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 845–851, 2004
A Convenient Synthesis of Octahydro-
pyrazino[1,2-a]pyrazine
Feng Liang,1 Xiao-Jun Wu,1 Shi-Wei Zhang,2
and Cheng-Tai Wu1,
*
1Department of Chemistry, Wuhan University, Wuhan, P.R. China
2State Key Laboratory for Structural Chemistry of Stable and
Unstable Species, Peking University, Beijing, P.R. China
ABSTRACT
Octahydro-pyrazino[1,2-a]pyrazine has been prepared by a new and
efficient method starting from 1,3-dichloro-2-propanol and N-tosylated
diethylenetriamine. The structure of title compound was determined by
spectroscopy and x-ray diffraction technique.
Key Words: Piperazine; Pyrazine; Macrocycle; Condensation;
Cyclization.
The piperazine structure is particularly attractive, since it is present in a
large number of biologically active compounds, and there is considerable
*
Correspondence: Cheng-Tai Wu, Department of Chemistry, Wuhan University,
Wuhan, 430072, P.R. China; E-mail: chemoliangf@yahoo.com.cn.
845
DOI: 10.1081/SCC-120028357
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Liang et al.
interest in the modification of the piperazine ring system.[1] The recent
research results suggest a series of octahydro-pyrazino[1,2-a]pyrazines are
useful as antiallergic agents.[2] Gubert et al. developed a route from 1,4-
dibenzyl-2-ethoxycarbonylpiperazine for the synthesis of this ring system.[3]
Under their conditions, this ring system was obtained with a low overall yield
in six steps. Optimization of synthetic route to this ring system is still
desirable.
Previously we have described a variety of interesting hydroxyl-sub-
stituted macrocyclic polyamines obtained by cyclization of 1,3-dichloro-2-
propanol with di(poly)-N-tosylamides in the presence of sodium ethoxide in
ethanol.[4,5] As an extension of this work, we employed three methods to
synthesize macrocycle 3. While we followed method (i), [2 þ 2] condensation
product 4 was isolated. However, the tosyl groups of macrocycle 3 were
removed by treatment with 33% HBr/AcOH in the presence of a large excess
of phenol to give octahydro-pyrazino[1,2-a]pyrazine 5 in high yield. The
synthetic routes are outlined in Sch. 1. Table 1 shows that the best reaction
condition is 48 hr for compound 5 formation.
The structure of compound 5 was established on the basis of spectro-
scopic data. The DEPT and gHSQC technique were employed to give us some
important information (Fig. 1). From the structural formula, the high field
signals at d42.24 can be assigned to C5 and C7; signals at d43.62 can be
Scheme 1. Reagents (yields): (i) NaOEt/EtOH (3, 45%; 4, 10%); (ii) K2CO3/
CH3CN or K2CO3/EtOH (3, 21%); (iii) KF-Al2O3/EtOH (3, 30–45%); (iv) HBr/
HOAc; PhOH (5, 10–63%; 6, 30–85%; 7, 90%).

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Synthesis of Octahydro-pyrazino[1,2-a]pyrazine
847
Table 1. The product distributions while the tosyl groups of
macrocycle 3 were removed.
Reaction time (hr)
24
36
48
72
96
Yield (%)
Compound 5
Compound 6
10
85
37
55
61
31
61
33
63
30
assigned to C1 and C3; signals at d49.51 can be assigned to C4 and C6; the low
field signal at d54.37 can be assigned to C2; and signal at d54.47 can be
1
assigned to DSS (as standard). The H NMR spectra lines of H protons are
complicated and hard to be assigned. In order to confirm the spectroscopic
results, the structure of compound 5 was determined by x-ray crystallography
showing one six-membered ring fused to the other six-membered ring in chair-
chair conformation.a Figure 2 gives the ORTEP drawing of the crystal
structure.
In conclusion, we have presented an efficient synthesis of octahydro-
pyrazino[1,2-a]pyrazine that was carried out in good overall yield without any
chromatography.
EXPERIMENTAL
General
Melting points were determined on an X4 microscope melting point
apparatus and temperature uncorrected. The IR spectra were recorded on a
aX-ray crystallograph for 5: C7H20Br3N3O, Mr ¼ 401.99, crystal, 0.30 Â 0.20 Â
˚
0.10 mm, monoclinic, Space group P2(1)/c, T ¼ 293(2) K, a ¼ 10.238(2) A,
3
˚
˚
˚
˚
b ¼ 9.5959(19) A, c ¼ 14.020(3) A, b ¼ 91.04(3) A, v ¼ 1377.2(5) A , Z ¼ 4,
l(MoKa) ¼ 0.71073 A, Dc ¼ 1.924 Mg/m , m ¼ 8.767 mm21, F(000) ¼ 784, 9573
3
˚
intensities, collected 2.578 , u , 27.488, R1 (I . 2s(I)) ¼ 0.0457, wR2 ¼ 0.0829,
s ¼ 0.849, largest diff. Peak and hole: 0.963 and 20.975 e A23. Atomic coordinates,
˚
bond angles, bond lengths and thermal parameters assisted to this compound have been
deposited at the Cambridge Crystallographic Data Centre in CIF file. CCDC number:
200701.

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Liang et al.
Figure 1. (a) The 13C DEPT spectra for compound 5 (with DSS as standard) in D2O
solution; (b) the gHSQC spectra for compound 5 (with DSS as standard) in D2O
solution.
1
Nicolet Avatar 360 FT-IR spectrometer. The H and 13C NMR spectra were
obtained on a Varian Mercury VX-300 MHz spectrometer using TMS as
internal standard. The MS spectra were recorded on a ZAB 3F-HF spectro-
meter. Elemental analyses were conducted on a Perkin–Elmer 204B
elemental analyzer.
Figure 2. The structure of 5 crystal. Only nonhydrogen atoms are shown.

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Synthesis of Octahydro-pyrazino[1,2-a]pyrazine
Preparation of N-tosyl Macrocycles 3 and 4
849
Method (i)
Compounds 3 and 4 were obtained following the procedure described in
Ref.[5]. 3: (45% yield), M.p. 210–2128C. IR (KBr, v, cm21): 3510, 1335,
1155, 1102. H NMR (CDCl3): d2.42 (s, 9H, ArCH3), 3.05–3.42 (m, 12H,
1
NCH2), 3.70 (s, 1H, OH), 4.46 (q, 1H, OCH), 7.20–7.81 (m, 12H, ArH). MS
(FAB); m/z (%): 623 (62) [M þ 1]þ. Anal. calcd. (%) for C28H35N3O7S3,
C 54.08, H 5.68, N 6.76; found: C 54.41, H 5.34, N 6.45. 4: (10% yield), M.p.
280–2828C. IR (KBr, v, cm21): 3521, 1331, 1150, 1096. 1H NMR (DMSO):
d2.42 (s, 18H, ArCH3), 3.02–3.20 (m, 24H, NCH2), 3.75 (s, 2H, OH), 5.20
(q, 2H, OCH), 7.20–7.78 (m, 24H, ArH). MS (FAB); m/z (%): 1245 (18)
[M þ 1]þ. Anal. calcd. (%) for C56H70N6O14S6, C 54.08, H 5.68, N 6.76;
found: C 53.80, H 5.49, N 6.54.
Method (ii)
N-tosylated diethylenetriamine 2 (1.13 g, 2 mmol) and K2CO3 (0.69 g,
5 mmol) were suspended in CH3CN (50 mL) under N2. To this mixture, a
solution of 1,3-dichloro-2-propanol 1 (0.26 g, 2 mmol) in CH3CN (50 mL) was
added at room temperature. The addition was completed over 2 hr after which
the suspension was stirred for a further 20 hr then filtered. The solution was
evaporated under vacuum and the residue was crystallized from EtOH giving
3 (0.25 g, 20.2% yield).
N-tosylated diethylenetriamine 2 and K2CO3 were suspended in refluxing
EtOH under N2. After the addition was complete, the suspension was refluxed
for 20 hr then filtered. The solution was evaporated under vacuum and the
residue was crystallized from EtOH giving 3 (21.1% yield).
Method (iii)
[6]
N-tosylated diethylenetriamine 2 (5.65 g, 10 mmol) and KF–Al2O3
(7.9 g) were suspended in refluxing EtOH (150 mL) under N2. To this mixture,
a solution of 1,3-dichloro-2-propanol 1 (1.30 g, 10 mmol) in EtOH (50 mL)
was added. The addition was completed over 2 hr after which the suspension
was refluxed for a further 20 hr then filtered. The solution was evaporated
under vacuum and the residue was crystallized from EtOH giving 3 (1.87 g,
30.1% yield).
The yield improved when 1,3-dichloro-2-propanol was replaced with 1,3-
dibromo-2-propanol (45.7% yield).

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Liang et al.
.
Preparation of Compounds 5 2HBr and 6 3HBr
.
The N-tosyl macrocycle 3 (1.24 g, 2 mmol), 33%HBr/AcOH (30 mL) and
phenol (2 g) were combined and stirred at 80–908C for 48–96 hr. After being
cooled to r.t., the solution was poured into dry Et2O (200 mL) to give the red
.
precipitate. 5 2HBr and 6 3HBr were separated by fractional crystallization
.
.
from EtOH : H2O (1 : 1 to 10 : 1) solutions. 5 2HBr (0.49 g, 60.9% yield). M.p.
.2808C (dec.). IR (KBr, v, cm21): 3447, 3172, 1410, 1075. 1H NMR (D2O):
d2.61–3.40 (m, 13H, NCH2, NCH). 13C NMR (D2O): d42.24 (C5, C7), 43.62
.
(C1, C3), 49.51 (C4, C6), 54.37 (C2). Anal. calcd. (%) for C7H15N3
.
3HBr H2O, C 20.02, H 5.29, N 10.01; found: C 20.22, H 5.41, N 10.14.
6 3HBr (0.25 g, 31.1% yield). M.p. .2808C (dec.). IR (KBr, v, cm21): 3435,
.
2932, 1457, 1137, 1044. 1H NMR (D2O): d 3.01–3.40 (m, 12H, NCH2), 4.21
.
(q, 1H, OCH). Anal. calcd. (%) for C7H17N3O 3HBr, C 20.02, H 5.29, N
10.01; found: C 20.27, H 5.61, N 9.84.
.
Preparation of Compound 7 6HBr
The N-tosyl macrocycle 4 (1.24 g, 1 mmol), 33%HBr/AcOH (30 mL) and
phenol (2 g) were combined and stirred at 80–908C for 24 hr. After being
cooled to r.t., the solution was poured into dry Et2O (200 mL) and the red
.
precipitate was recrystallized from EtOH to give 7 6HBr (0.72 g, 89.6%
yield). M.p. .2808C (dec.). IR (KBr, v, cm21): 3422, 2999, 1443, 1127, 1023.
1H NMR (D2O): d3.21–3.62 (m, 24H, NCH2), 4.88 (q, 2H, OCH). Anal.
.
calcd. (%) for C14H34N6O2 6HBr, C 20.92, H 5.02, N 10.45; found: C 20.73,
H 4.91, N 10.29.
ACKNOWLEDGMENTS
This research was supported by the National Science Foundation of China
(No. 29972034).
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Received in the USA August 22, 2003

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