A short, novel approach to 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a] quinoline-4,6-diones

Article abstract of DOI:10.1055/s-2004-831308

An expeditious route to constrained arylpiperazinones has been developed. The key reaction formed the tricyclic system in one-pot via a 1,4-addition-lactamization-aromatic substitution sequence. Four examples were prepared.

Full text of DOI:10.1055/s-2004-831308

LETTER
2165
A Short, Novel Approach to 2,3,4a,5-Tetrahydro-1H-pyrazino[1,2-a]
quinoline-4,6-diones
An
A
pproach to 2
o
, 3,4a,5-Tetr
n
ahydro-1
H
-p
a
yrazino[1,2
l
-
a
]quin
d
oline-4,6-diones C. Bernotas*a,1
Aventis Pharmaceuticals, Box 6800, Route 202-206, Bridgewater, NJ 08807, USA
Fax +1(484)8659399; E-mail: bernotr@wyeth.com
Received 4 May 2004
the ring system found in 5. Some time ago, Phillips5 re-
ported that addition of ethylenediamine to diethylfuma-
rate 7a readily afforded piperazinone 8a directly
(Scheme 2). This suggested that replacing one of the
ethoxy groups in 7a with an ortho-fluoroaryl ring (7b) and
reaction of 8a with ethylenediamine should provide 8b by
a 1,4-addition to the more reactive enone (as opposed to
the acrylate) followed by lactamization. Based on previ-
ous experience with the nitrone approach, it was anticipat-
ed that 8b would then undergo a facile intramolecular
SNAr reaction providing 5a. This paper describes the suc-
cessful application of this route to the synthesis of tricy-
clic systems 5.
Abstract: An expeditious route to constrained arylpiperazinones
has been developed. The key reaction formed the tricyclic system in
one-pot via a 1,4-addition–lactamization–aromatic substitution se-
quence. Four examples were prepared.
Key words: 1,4-additions, nucleophilic aromatic substitutions, cy-
clizations, lactams, medicinal chemistry
Arylpiperazines are a common motif found in G-protein-
coupled receptor (GPCR) ligands.2 As part of a program
directed toward expanding libraries of such potential
GPCR ligands, developing new approaches to constrained
arylpiperazines 6 was of considerable interest.3 Previous-
ly, a novel cycloaddition route to this class of compounds
utilizing nitrone 1 was described.4 Reaction of 1 with
TMS-enol ether 2 afforded isoxazolidine 3 (Scheme 1).
The nitrogen-oxygen bond in 3 was reductively cleaved to
reveal ortho-fluorophenone 4. This compound underwent
a facile intramolecular SNAr reaction to provide 5, a
2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-di-
one. Ultimately, this compound was reduced to final tar-
get 6.
H
N
O
H
N
EtO
O
O
O
N
N
H
X
O
O
X
7a X = OEt
7b X = Ar
8a X = OEt
8b X = Ar
5a (R = H)
Scheme 2
A need for a shorter and potentially more versatile synthe-
sis led to the investigation of other ways of constructing
The requisite precursors to the cyclization reaction were
readily made in two steps (Scheme 3). Addition of ortho-
fluorobenzaldehyde 9a to the lithium anion of ethyl propi-
olate, generated with LDA in THF at –78 °C, afforded
propargylic alcohol 10a.6 This alcohol was rearranged to
enone 11a by treatment with 2 equivalents of triethyl-
amine in dioxane at 55–60 °C for 6–8 hours. The presence
of an ortho-fluoro substituent seemed to retard rearrange-
ment since several hours of heating were required for the
reaction to approach completion rather than the shorter
time at ambient temperature reported for the unsubstituted
phenyl ring.7
O
F
R
N
NR
O
OTMS
F
2
N
N
O
OTMS
O
3
1
NR
R
N
H
N
O
O
HN
F
N
N
With the enone in hand, the cyclization strategy was ex-
amined. Compound 11a in DMF was treated with 1.1
equivalents of ethylenediamine and heated at 60 °C for 6
hours. The reaction was then cooled resulting in precipi-
tate formation. Addition of diethyl ether followed by suc-
tion filtration and ether trituration of the solid gave
2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-di-
one (5a) in good yield.8
O
O
4
5
6
R = CH2Ph
Scheme 1
SYNLETT 2004, No. 12, pp 2165–2166
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831308; Art ID: S03904ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
0
.2
0
0
4
After this initial success, three other analogs with addi-
tional substituents on the aromatic ring were investigated.
Under conditions similar to those employed for 9a, ortho-

2166
R. C. Bernotas
LETTER
fluorobenzaldehydes 9b–d were converted into alcohols
10b–d and then rearranged to enones 11b–d. The enones
were reacted with ethylenediamine to provide 5b–d, also
in moderate yield.
References
(1) Current address: R. C. Bernotas, Wyeth Pharmaceuticals,
500 Arcola Road, Collegeville, PA 19426, USA.
(2) Glennon R. A., Dukat M., Westkaemper R. B.; In
Psychopharmacology: The Fourth Generation of Progress;
Bloom F. E., Kupfer D. J.; Raven Press: New York, 1999;
CD-ROM edition.
(3) (a) Rupe, H.; Thommen, W. Helv. Chim. Acta 1947, 30,
920. (b) Baxter, C. A. R.; Richards, H. C. J. Med. Chem.
1972, 15, 351. (c) Huff, J. R.; King, S. W.; Saari, W. S.;
Springer, J. P.; Martin, G. E.; Williams, M. J. Med. Chem.
1985, 28, 945.
OH
O
CO2Et
H
CO2Et
LDA/THF
F
F
X
X
7a X = H
8a X = H (71%)
7b X = 3-F
7c X = 4-Cl
7d X = 4-OMe
8b X = 3-F (69%)
8c X = 4-Cl (69%)
8d X = 4-OMe (60%)
(4) Bernotas, R. C.; Adams, G. Tetrahedron Lett. 1996, 37,
7343.
(5) (a) Phillips, A. P. U.S. Patent 2,958, 693; Chem. Abstr. 1961,
55, 9438a. (b) Okawara, T.; Matsumoto, S.; Yamasaki, T.;
Furukawa, M. Heterocycles 1989, 29, 1601.
O
(6) Barua, N. C.; Schmidt, R. R. Synthesis 1986, 891.
(7) (a) Nineham, A. W.; Raphael, R. A. J. Chem. Soc. 1949,
118. (b) Acardi, A.; Cacchi, S.; Marinelli, F.; Misiti, D.
Tetrahedron Lett. 1988, 29, 1457.
Et3N
CO2Et
dioxane/60 °C
F
X
(8) All compounds gave satisfactory spectral data (1H NMR, 13
NMR, and 19F NMR, IR, and CI-MS). Spectral data for
representative compounds: 10a (gradually decomposes in
CDCl3): 1H NMR (CDCl3): d = 7.59 (1 H, dt, J = 2.0, 7.9
Hz), 7.29 (1 H, m), 7.15 (1 H, t, J = 7.9 Hz), 7.04 (1 H, t,
C
9a X = H (95%)
9b X = 3-F (81%)
9c X = 4-Cl (72%)
9d X = 4-OMe (63%)
H
J = 8.9 Hz), 5.80 (1 H, s), 4.20 (2 H, q, J = 7.1 Hz), 1.31 (3
H, t, J = 7.1 Hz) ppm. 13C NMR (CDCl3): d = 159.8 (d,
J = 249 Hz, F-coupled), 153.4, 130.6 (d, J = 9.0 Hz),
128.4 (d), 126.1 (d, J = 13.0 Hz, F-coupled), 124.5, 115.6
(d, J = 21.0 Hz, F-coupled), 85.4, 77.3, 62.3, 58.3, 13.91
ppm. 19F NMR (CDCl3): d = –118.1 ppm. MS (CI/CH4):
m/z (%) = 223 (30) [M + H], 205 (100) [M + H – H2O]. IR:
1712, 1613, 1589 cm–1. Compound 11a: 1H NMR (CDCl3):
d = 7.81 (1 H, dt, J = 2.0, 8.9 Hz), 7.74 (1 H, dd, J = 3.3, 15.6
Hz), 7.57 (1 H, m), 7.25 (1 H, t, J = 7.9 Hz), 7.15 (1 H, dd,
J = 8.9, 10.9 Hz), 6.83 (1 H, dd, J = 2.0, 8.9 Hz), 4.30 (2 H,
q, J = 7.1 Hz), 1.35 (3 H, t, J = 7.1 Hz) ppm. 13C NMR
(CDCl3): d = 188.1, 165.4, 163.4, 160.0, 139.1 (d), 135.2 (d),
131.6 (d, J = 48 Hz, F-coupled), 125.6 (d, J = 6.0 Hz, F-
coupled), 124.7, 116.7 (d, J = 22.0 Hz, F-coupled), 61.3,
14.1 ppm. 19F NMR (CDCl3): d = –109.2 ppm. MS (APCI):
m/z (%) = 223 (100) [M + H]. IR: 1724, 1672, 1610 cm–1.
Compound 5a: 1H NMR (DMSO-d6): d = 8.18 (1 H, br s),
7.75 (1 H, d, J = 7.8 Hz), 7.50 (1 H, t, J = 7.8 Hz), 7.15 (1 H,
d, J = 8.0 Hz), 6.85 (1 H, t, J = 7.8 Hz), 4.13 (1 H, br d), 4.06
(1 H, dd, J = 4.9, 12.8 Hz), 3.43 (1 H, app dt, J = 5.9, 11.8
Hz), 3.30 (1 H, br d), 3.10 (1 H, app dt, J = 4.0, 11.4 Hz),
2.91 (1 H, dd, J = 4.9, 16.8 Hz), 2.76 (1 H, dd, J = 12.8, 16.7
Hz) ppm. 13C NMR (DMSO-d6): d = 192.1, 167.8, 151.3,
135.6, 127.3, 120.3, 118.2, 114.3, 58.3, 42.1, 39.9, 39.2
(partly obscured by DMSO pattern) ppm. MS (APCI): 217
(100) [M + H]. IR: 1723, 1679, 1623 cm–1.
N
O
H2NCH2CH2NH2
DMF/60 °C
N
O
X
6a X = H (64%)
6b X = 3-F (56%)
6c X = 4-Cl (53%)
6d X = 4-OMe (54%)
Scheme 3
In conclusion, a new and expeditious route to 2,3,4a,5-tet-
rahydro-1H-pyrazino[1,2-a]quinoline-4,6-diones (5) has
been developed. The key step in this approach to con-
strained arylpiperazinones was a cascade sequence of
three reactions that constructed the tricyclic ring system:
1,4-addition, lactamization, and intramolecular SNAr-type
reaction. This work may be useful for synthesizing other
related ring systems.
Synlett 2004, No. 12, 2165–2166 © Thieme Stuttgart · New York