Synthesis of hexahydropyrazino[1,2-b]isoquinolines as simplified saframycin analogues

Article abstract of DOI:10.1055/s-0033-1340070

Various hexahydropyrazino[1,2-b]isoquinolines were synthesised as simplified saframycin analogues. Construction of this core proceeded through a tetrahydroisoquinoline synthesis followed by acylation/alkylation of the tetrahydroisoquinoline nitrogen and subsequent ring closure using various aliphatic and aromatic amines. The resulting piperazinones were reacted with LiAlH₄ or LiAlH(OEt)₃ to synthesise further analogues. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340070

LETTER
▌69
lSetyternthesis of Hexahydropyrazino[1,2-b]isoquinolines as Simplified Saframycin
Analogues
Synthesis of Hexahydropyrazino[1,2-b]isoquinolines
Tuyen Nguyen Van,1 Pieter Claes, Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
9000 Ghent, Belgium
Fax +32(9)26462 21; E-mail: norbert.dekimpe@ugent.be
Received: 12.07.2013; Accepted after revision: 01.10.2013
analogues. In initial studies, ethyl N-(diphenylmeth-
Abstract: Various hexahydropyrazino[1,2-b]isoquinolines were
ylene)glycinate (4) failed to react with bromomethyl de-
synthesised as simplified saframycin analogues. Construction of
rivatives 5 (Na or KHMDS, –78 °C or 0 °C9) but complete
conversion was obtained upon reaction with KOH in
this core proceeded through a tetrahydroisoquinoline synthesis fol-
lowed by acylation/alkylation of the tetrahydroisoquinoline nitro-
gen and subsequent ring closure using various aliphatic and H2O–CH2Cl2 using Bu4NHSO4 as a phase-transfer cata-
aromatic amines. The resulting piperazinones were reacted with
LiAlH4 or LiAlH(OEt)3 to synthesise further analogues.
lyst. Tetrahydroisoquinoline 7a was synthesised by means
of a Pictet–Spengler reaction starting from 1-bromometh-
yl-2,5-dimethoxy-3,4-dimethylbenzene (5a)10a via inter-
Key words: saframycins, piperazinones, diketopiperazines, cycli-
sation, tetrahydroisoquinolines
mediate amine 6 in a yield of 76% over two steps.
Tetrahydroisoquinolines 7b–d were synthesised by reac-
tion of bis(bromomethyl)benzene derivatives 5b–d10b–e
Saframycins 1, isolated from Streptomyces lavendulae, with ethyl N-(diphenylmethylene)glycinate (4) under ba-
belong to a family of microbial fermentation products sic conditions followed by acid-induced ring closure in
with a remarkable antiproliferative activity. The most ac-
tive derivative is saframycin A (1a), a bisquinone alkaloid
OMe
bearing an α-aminonitrile function.2 The mode of activity
O
Me
O
is connected to the iminium ions generated from this
α-aminonitrile unit thus covalently modifying DNA.
Quinoid alkaloids with antiproliferative activity such as
the ecteinascidines,3 isolated from the marine tunicate
Ecteinascidia turbinata, have raised new interest towards
the synthesis of saframycin analogues.
O
H
H
Me
N
Me
R1
N
R2
MeO
H
H
O
NH
HO
O
Trabectedin (2; also known as ecteinascidin 743 or ET-743)
is an antitumor drug approved for the treatment of ad-
vanced soft-tissue sarcoma. It is sold by Zeltia and John-
son & Johnson under the brand name Yondelis for the
treatment of advanced soft-tissue sarcoma. Currently,
simplified analogues such as phthalascidin (3) are known,
bearing a similar activity4 (Figure 1).
O
NH
S
OMe
Me
MeO
Me
HO
H
O
AcO
H
saframycin
O
Me
A (1a) R1 = CN, R2 = H
B (1b) R1 = R2 = H
C (1c) R1 = H R2 = OMe
G (1d) R1 = CN, R2 = OH
S (1e) R1 = OH, R2 = H
N
Me
N
O
H
OH
O
All these compounds can be considered as dimers of
structurally less complex tetrahydroisoquinoline subunits.
Synthesis of this kind of simplified analogues has re-
ceived little attention as most work focusses on total syn-
thesis.5 Nevertheless, related piperazinones and diketo-
piperazines have been prepared before6 and pyrazino[1,2-
b]isoquinolines have been examined for cytotoxicity.7
Therefore, the synthesis of quinone-type derivatives un-
der their hydroquinone methyl ether form was envisaged.
ecteinascidin 743 (2)
OMe
Me
HO
H
AcO
Me
H
N
H
Me
N
O
O
CN
We recently reported the synthesis of functionalised di-
ketopiperazines as cyclotryprostatin and tryprostatin ana-
logues.8 It was subsequently envisaged to apply this
methodlogy to the synthesis of simplified saframycin
N
O
O
phthalascidin (3)
SYNLETT 2014, 25, 0069–0074
Advanced online publication: 13.11.2013
DOI: 10.1055/s-0033-1340070; Art ID: ST-2013-D0646-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 1 Examples of saframycins 1, trabectedin (ecteinascidin 743,
2), and the structurally related phthalascidin (3)

70
T. Nguyen Van et al.
LETTER
60–80% yields.11 Next, the nitrogen atom was acylated Starting from N-(2-bromoethyl)tetrahydroisoquinolines
with chloroacetyl chloride to afford N-chloroacetyl tetra- 9, a range of piperazinones 11 was synthesised in high, al-
hydroisoquinolines 8 in 50–70% yield12 or alkylated with beit somewhat lower yields than diketopiperazines 10
1,2-dibromoethane to yield N-(2-bromoethyl)tetra- (Table 2).15
hydroisoquinolines 9 in 70–94% yield13 (Scheme 1). Fi-
nally, N-chloroacetyl tetrahydroisoquinolines 8 were
The lactam function of piperazinones 11 was further re-
duced to create additional saframycin analogues. Reaction
reacted with various primary amines in EtOH towards
with LiAlH4 resulted in complete reduction of the lactam
diketopiperazines 10 in good to excellent yields (Table 1).14
moiety leading to piperazines 14 in 70–80% yield.16 Re-
action with the less reactive LiAlH(OEt)3 gave the hemi-
aminals, which were further converted into aminonitriles
CO2Et
N
OMe
OMe
OMe
13 with potassium cyanide and acetic acid.17 One piperaz-
inone was demethylated with boron(III) bromide fol-
lowed by oxidation with HNO3 to yield quinone 12
(Scheme 2).18
CO2Et
NH2
a, b
Br
+
Ph
Ph
OMe
OMe
4
5a
6 (92%)
O
O
R2
c
N
a, b
CO2Et
N
OMe
N
R1
R1
R1
CO2Et
d, e
Br
Br
O
+
NH
R1
Ph
Ph
12 R2 = Bn (68%)
OMe
OMe
OMe
OMe
O
R2
R2
5b R1 = H
5c R1 = Br
7a R1 = Me (83%)
7b R1 = H (80%)
7c R1 = Br (66%)
4
c
N
N
N
N
OMe
OMe
OMe
g
f
14a R2 = n-Pr (80%)
11
d, e
OMe
OMe
R1
R1
CO2Et
R1
R1
CO2Et
CN
N
N
R2
Br
Cl
N
OMe
OMe
O
N
9a R1 = Me (54%)
9b R1 = H (70%)
8a R1 = Me (85%)
8b R1 = H (93%)
8c R1 = Br (94%)
OMe
13a R2 = n-Pr (84%)
13b R2 = Ph(CH2)2 (85%)
13c R2 = 4-ClC6H4(CH2)2 (79%)
CO2Et
N
OMe
OMe
OMe
O
OMe
CO2Et
d, e
Br
Br
R2
R2
+
c
N
N
NH
Ph
Ph
N
N
OMe
OMe
OMe
OMe
4
5d
7d (60%)
g
14b R2 = n-Pr (80%)
14c R2 = n-Bu (70%)
14d R2 = 4-ClC6H4(CH2)2 (75%)
11
f
d, e
OMe
OMe
OMe
OMe
CO2Et
CO2Et
O
CN
N
R2
N
N
N
Br
Cl
OMe
OMe
9d (50%)
8d (70%)
13d R2 = n-Pr (78%)
13e R2 = 4-ClC6H4(CH2)2 (85%)
Scheme 1 Reagents and conditions: a) 30% aq KOH, Bu4NHSO4 (1
equiv), CH2Cl2, r.t., 12 h; b) HCl (2 M) THF, r.t., 15 h; c) 37% HCHO
in H2O (2 equiv), TFA (2 equiv), CH2Cl2, Δ, 2 h; d) 30% aq KOH,
Bu4NHSO4 (1 equiv), CH2Cl2, r.t., 30 min; e) HCl (2 M) THF, r.t., 30
min; f) ClCH2COCl (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, r.t., 2 h; g)
BrCH2CH2Br (20 equiv), K2CO3 (1 equiv), neat, 80 °C, 24 h.
Scheme 2 Reagents and conditions: a) BBr3 (2.1 equiv), –78 °C, 1 h,
then 0 °C, 45 min; b) HNO3 (10 M), r.t., 45 min; c) LiAlH4 (4 equiv),
Et2O, r.t., 4 h; d) LiAlH(OEt)3 (10 equiv), THF, 0 °C, 30 min; e)
AcOH (40 equiv), KCN (6 equiv), H2O, r.t., 3 h.
Synlett 2014, 25, 69–74
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Hexahydropyrazino[1,2-b]isoquinolines
71
Table 1 Synthesis of Diketopiperazines 10
OMe
O
OMe
R1
R1
R2
N
R1
R1
CO2Et
O
R2NH2 (3–5 equiv)
EtOH, r.t., 24–36 h
N
O
N
Cl
OMe
OMe
10a–r
8a–d
Compd
R1, R1
R2
Time (h)
Yield (%)
10a
10b
10c
10d
10e
10f
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
H, H
n-Pr
24
24
24
24
24
24
24
24
24
24
36
36
36
36
36
24
24
24
87
92
73
78
86
86
82
85
77
72
98
82
86
78
79
85
81
75
n-Bu
Bn
4-ClC6H4CH2
Ph(CH2)2
n-Pr
10g
10h
10i
H, H
n-Bu
H, H
Bn
H, H
4-ClC6H4CH2
Ph(CH2)2
n-Pr
10j
H, H
10k
10l
Br, Br
Br, Br
n-Bu
10m
10n
10o
10p
10q
10r
Br, Br
Bn
Br, Br
4-ClC6H4CH2
Ph(CH2)2
n-Pr
Br, Br
–HC=CH–CH=CH–
–HC=CH–CH=CH–
–HC=CH–CH=CH–
Bn
4-ClC6H4CH2
In summary, a library of hexahydropyrazino[1,2-b]iso- were further reacted with LiAlH4 to obtain piperazines or
quinolines has been synthesised as representative simpli- LiAlH(OEt)3 and KCN to insert an α-aminonitrile func-
fied saframycin analogues. Both piperazinones and tion.
diketopiperazines were synthesised. The piperazinones
Table 2 Synthesis of Piperazinones 11
OMe
O
OMe
R1
R1
R2
R1
R1
CO2Et
R2NH2 (3–5 equiv)
EtOH, r.t., 24 h
N
N
N
Br
OMe
OMe
9a,b,d
11a–k
Compd
R1, R1
R2
Yield (%)
11a
11b
11c
11d
Me, Me
H, H
n-Pr
n-Pr
n-Bu
Bn
75
79
70
59
H, H
H, H
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 69–74

72
T. Nguyen Van et al.
LETTER
Table 2 Synthesis of Piperazinones 11 (continued)
OMe
OMe
O
OMe
R1
R1
R2
R1
R1
CO2Et
R2NH2 (3–5 equiv)
EtOH, r.t., 24 h
N
N
N
Br
OMe
9a,b,d
11a–k
Compd
R1, R1
R2
Yield (%)
11e
11f
11g
11h
11i
H, H
H, H
H, H
H, H
4-ClC6H4CH2
Ph(CH2)2
65
75
63
74
72
70
75
4-ClC6H4(CH2)2
2,5-(MeO)2C6H3(CH2)2
n-Pr
–HC=CH–CH=CH–
–HC=CH–CH=CH–
–HC=CH–CH=CH–
11j
11k
n-Bu
4-ClC6H4CH2
C. Bioorg. Med. Chem. 2008, 16, 9065. (c) Ortín, I.;
González, J. C.; de la Cuesta, E.; Avendaño, C. Bioorg. Med.
Chem. 2010, 18, 6813.
Acknowledgment
The authors are indebted to the Janssen Research Foundation
(Johnson & Johnson) for financial support.
(8) Nguyen Van , T.; Claes, P.; De Kimpe, N. Synlett 2013, 24,
1006.
(9) Mash, E. A.; Williams, L. J.; Pfeiffer, S. S. Tetrahedron Lett.
1997, 38, 6977.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(10) (a) Syper, L.; Mlochowski, J.; Kloc, K. Tetrahedron 1983,
39, 781. (b) Ardecky, R. J.; Kerdesky, F. A. J.; Cava, M. P.
J. Org. Chem. 1981, 46, 1483. (c) Eskildse, J.; Christensen,
T.; Reenberg, T.; Larsen, U.; Christensen, J. B. Org. Prep.
Proced. Int. 2000, 32, 398. (d) Mendez-Rojas, M. A.;
Ejsmont, K.; Watson, W. H. J. Chem. Crystallogr. 2002, 32,
177. (e) Claessens, S.; Jacobs, J.; Van Aeken, S.; Abbaspour
Tehrani, K.; De Kimpe, N. J. Org. Chem. 2008, 73, 7555.
(11) Ethyl 5,8-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (7b)
References and Notes
(1) Current address: Institute of Chemistry, Vietnam Academy
of Science & Technology, 18 Hoang Quoc Viet, Cau Giay,
Ha Noi, Viet Nam.
(2) (a) Arai, T.; Takahashi, K.; Kubo, A. J. Antibiot. 1977, 30,
1015. (b) Arai, T.; Takahashi, K.; Ishiguro, K.; Yazawa, K.
J. Antibiot. 1980, 33, 951. For a review on
tetrahydroisoquinoline antitumor antibiotics, see: (c) Scott,
J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(3) (a) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.;
Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org.
Chem. 1990, 55, 4508. (b) Rinehart, K. T.; Holt, T. G.;
Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.;
Martin, D. G. J. Org. Chem. 1990, 55, 4512. (c) Garcia-
Rocha, M.; Garcia-Gravalos, M. D.; Avila, J. Brit. J. Cancer
1996, 73, 875. (d) Schwartsmann, G.; Brondani da Rocha,
A.; Berlinck, R. G. S.; Jimeno, J. Lancet Oncol. 2001, 2, 221.
(e) Rinehart, K. L. Med. Res. Rev. 2000, 20, 1.
(4) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc.
Natl. Acad. Sci. U.S.A. 1999, 98, 3496.
(5) (a) Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.;
Nakamura, M. J. Org. Chem. 1988, 53, 4295. (b) Saito, N.;
Harada, S.; Inouye, I.; Yamaguchi, K.; Kubo, A.
To a solution of ethyl N-(diphenylmethylene)glycinate (4,
801 mg, 3 mmol), freshly recrystallized 2,3-bisbromo-
methyl-1,4-dimethoxybenzene (5b, 972 mg, 3 mmol), and
Bu4NHSO4 (1017 mg, 3 mmol) in CH2Cl2 (10 mL) was
added an aq solution of KOH (30%, 5 mL). The reaction
mixture was stirred at r.t. for 30 min. Next, the mixture was
poured onto H2O and exhaustively extracted with CH2Cl2.
The combined organic phases were washed with sat. aq
NaHCO3, dried (MgSO4), filtered, and evaporated in vacuo.
To this crude residue was added THF (20 mL) and HCl (2 M,
20 mL). The reaction mixture was stirred at r.t. for 30 min
and subsequently neutralized by treatment with a solution of
aq Na2CO3 (2 M). Next, the solvent was evaporated in
vacuo, and the residue was exhaustively extracted with
EtOAc. The combined organic phases were washed with sat.
aq NaHCO3, dried (MgSO4), filtered, and evaporated in
vacuo. This crude mixture was purified column
chromatography on silica (hexane–EtOAc) to obtain ethyl
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (7b, 637 mg,
80%).
Tetrahedron 1995, 51, 8231. (c) Obika, S.; Yasui, Y.;
Yanada, R.; Takemoto, Y. J. Org. Chem. 2008, 73, 5206.
(d) Martinez, E. J.; Corey, E. J. Org. Lett. 1999, 1, 75.
(e) Dong, W.; Liu, W.; Liao, X.; Guan, B.; Chen, S.; Liu, Z.
J. Org. Chem. 2011, 76, 5363.
Note: In order to obtain a good yield, it is of utmost
importance to use freshly recrystallized starting materials 4
and 5.
(6) Huck, L.; González, J. F.; de la Cuesta, E.; Menéndeza, J. C.;
Avendaño, C. Org. Biomol. Chem. 2011, 9, 6271.
(7) (a) González, J. F.; de la Cuesta, E.; Avendaño, C. Bioorg.
Med. Chem. 2007, 15, 112. (b) Ortín, I.; González, J. C.; de
la Cuesta, E.; Manguan-García, C.; Perona, R.; Avendaño,
Analytical Data
Colourless crystals; mp 90.5–91 °C. 1H NMR (270 MHz,
CDCl3): δ = 1.31 (3 H, t, J = 7.0 Hz, Me), 1.63 (1 H, br s,
Synlett 2014, 25, 69–74
© Georg Thieme Verlag Stuttgart · New York

LETTER
NH), 2.64 (1 H, dd, J = 9.9, 16.5 Hz, H-4a), 3.09 (1 H, dd,
Synthesis of Hexahydropyrazino[1,2-b]isoquinolines
m, OCH2), 6.60 (1 H, d, J = 9.1 Hz, H-6), 6.62 (1 H, d,
73
J = 16.5, 4.6 Hz, H-4b), 3.59 (1 H, dd, J = 4.6, 9.9 Hz, H-3),
3.76 (3 H, s, OMe), 3.78 (3 H, s, OMe), 3.80 (1 H, d, J = 15.8
Hz, H-1a), 3.84 (1 H, d, J = 15.8 Hz, H-1b), 4.19–4.27 (2 H,
m, OCH2), 6.60 (1 H, d, J = 8.9 Hz, H-6) 6.64 (1 H, d, J = 8.9
Hz, H-7). 13C NMR (68 MHz, CDCl3): δ = 14.2 (Me), 26.3
(C-4), 42.9 (C-1), 55.3 (C-3), 55.4 (OMe), 55.6 (OMe), 60.9
(OCH2), 106.9 and 107.2 (C-6, C-7), 123.7 and 125.1 (C-5a,
C-8a), 149.9 (=COMe), 151.2 (=COMe), 173.3 (C=O). IR
(KBr): ν = 3250 (NH), 2971, 2954, 2829, 1724 (C=O), 1605,
1484, 1464, 1438, 1260, 1225, 1182, 1091 cm–1. MS: m/z
(%) = 266 (100) [M + H+], 262 (20), 261 (20), 192 (20).
HRMS (ES+): m/z calcd for [C16H22NO4]+: 266.1392; found:
266.1396. Spectroscopic data are in accordance with
literature data: Al-Horani, R. A.; Desai, U. R. Tetrahedron
2012, 68, 2027.
J = 9.1 Hz, H-7). 13C NMR (75 MHz, CDCl3): δ = 14.4 (Me),
25.8 (C-4), 30.3 (C-1′), 46.9 (C-1), 55.5 (OMe), 55.8 (OMe),
57.1 (CBr), 59.7 (C-3), 60.7 (OCH2), 107.0 and 107.4 (C-6,
C-7), 122.6 and 123.8 (C-5a, C-8a), 150.1 (=COMe), 151.2
(=COMe), 172.5 (C=O). IR (NaCl): ν = 2930, 1731 (C=O),
1650, 1483, 1464, 1438, 1257, 1181, 1082 cm–1. MS m/z (%)
372/374 (M+H+, 10), 310 (7), 393 (15), 392 (100). HRMS
(ES+): m/z calcd for [C20H14NO2]+: 300.1025; found:
300.1027.
(14) 7,10-Dimethoxy-8,9-dimethyl-2-propyl-2,3,11,11a-
tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione
(10a)
A mixture of ethyl 2-(2-chloroacetyl)-5,8-dimethoxy-6,7-
dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a,
184.5 mg, 0.5 mmol) and n-propylamine (132.5 mg, 2.5
mmol) in anhydrous EtOH (10 mL) was stirred for 24 h at r.t.
Then, the mixture was poured onto H2O and exhaustively
extracted with EtOAc. The combined organic phases were
washed, dried (MgSO4), filtered, and evaporated in vacuo.
Purification by chromatography on silica (hexane–EtOAc)
gave pure 7,10-dimethoxy-8,9-dimethyl-2-propyl-
2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-
dione (10a, 150 mg, 87%).
(12) Ethyl 2-(2-Chloroacetyl)-5,8-dimethoxy-6,7-dimethyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a)
A mixture of ethyl 5,8-dimethoxy-6,7-dimethyl-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (7a, 586 mg, 2 mmol)
and Et3N (222 mg, 2.2 mmol) in anhydrous CH2Cl2 (10 mL)
was cooled to 0 °C and chloroacetyl chloride (264 mg, 2.2
mmol) was added dropwise. The reaction mixture was
stirred at r.t. for 2 h. Then the mixture was poured onto H2O
and exhaustively extracted with CH2Cl2. The combined
organic phases were washed with sat. NaHCO3, dried
(MgSO4), filtered, and evaporated in vacuo. Purification by
column chromatography on silica (hexane–EtOAc) gave
pure ethyl 2-(2-chloroacetyl)-5,8-dimethoxy-6,7-dimethyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a, 688 mg,
93%).
Analytical Data
White powder, mp 169–169.5 °C. 1H NMR (270 MHz,
CDCl3): δ = 0.96 (3 H, t, J = 7.3 Hz, H-3), 1.57–1.68 (2 H,
m, 2 × H-2′), 2.18 (6 H, s, 2 × Me), 2.74 (1 H, dd, J = 12.2,
16.4 Hz, H-11a), 3.28–3.47 (2 H, m, H-1′a, H-1′b), 3.59 (1
H, dd, J = 3.4, 16.4 Hz, H-11b), 3.66 (3 H, s, OMe), 3.71 (3
H, s, OMe), 4.04 (2 H, s, H-3a, H-3b), 4.10 (1 H, d, J = 17.5
Hz, H-6a), 4.17 (1 H, dd, J = 12.2, 3.6 Hz, H-12), 5.40 (1 H,
d, J = 17.5 Hz, H-6b). 13C NMR (68 MHz, CDCl3): δ = 11.1
(C-3′), 12.45 (Me), 12.54 (Me), 19.8 (C-2′), 28.5 (C-11),
40.1 (C-6), 47.6 (C-1′), 49.4 (C-3), 55.6 (C-12), 60.3 (2 ×
OMe), 122.9 and 123.9 (C-7a, C-10a), 129.3 and 129.5 (C-
8, C-9), 151.0 (=COMe), 152.1 (=COMe), 162.3 (C=O),
165.0 (C=O). IR (KBr): ν = 2958, 2834, 1661 (C=O), 1658
(C=O), 1479, 1465, 1334, 1260, 1274, 1086, 1061 cm–1. MS:
m/z (%) = 347 (30) [M + H], 345 (70), 314 (15), 218 (35),
191 (100), 176 (70), 124 (50), 83 (70). HRMS (ES+): m/z
calcd for [C19H27N2O4]+: 347.1971; found: 347.1981.
(15) 7,10-Dimethoxy-2-propyl-3,4,11,11a-tetrahydro-2H,6H-
pyrazino[1,2-b]isoquinolin-1-one (11b)
Analytical Data
1H NMR (300 MHz, CDCl3): δ = 1.15 (3 H, t, J = 6.9 Hz,
Me), 2.17 (6 H, s, 2 × Me), 2.90 (1 H, dd, J = 5.9, 16.5 Hz,
H-4a), 3.47 (1 H, dd, J = 3.0, 16.5 Hz, H-4b), 3.65 (3 H, s,
OMe), 3.68 (3 H, s, OMe), 4.00–4.17 (2 H, m, OCH2), 4.24
(1 H, d, J = 12.5 Hz, H-1a), 4.29 (1 H, d, J = 12.5 Hz, H-1b),
4.73 (2 H, br s, 2 × H-2′), 5.46 (1 H, dd, J = 3.0, 5.9 Hz, H-
3). 13C NMR (75 MHz, CDCl3): δ = 12.51 (Me), 12.54 (Me),
14.0 (OCH2Me), 24.8 (C-4), 41.2 (C-2′), 41.4 (C-1), 51.3 (C-
3), 60.4 (2 × OMe), 61.4 (OCH2), 122.6 and 123.2 (C-5a, C-
8a), 129.2 and 129.8 (C-6, C-7), 150.6 (=COMe), 152.0
(=COMe), 166.6 and 170.3 (2 × C=O). IR (NaCl): ν = 2942,
2838, 1738 (C=O), 1732 (C=O), 1660, 1652, 1606, 1486,
1483, 1260, 1203, 1096 cm–1. MS: m/z (%) = 370/372 (100)
[M + H+], 324 (20), 296 (55), 294 (80), 266 (30), 220 (10).
HRMS (ES+): m/z calcd for [C18H2535ClNO5]+: 372.1392;
found: 372.1401.
A mixture of ethyl 2-(2-bromoethyl)-5,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (9b) (186 mg, 0.5
mmol) and n-propylamine (132.5 mg, 2.5 mmol) in
anhydrous EtOH (10 mL) was stirred for 24 h at r.t. Then, the
mixture was poured onto H2O and exhaustively extracted
with EtOAc. The combined organic phases were washed,
dried (MgSO4), filtered, and evaporated in vacuo.
Purification by chromatography on silica (hexane–EtOAc)
gave pure 7,10-dimethoxy-2-propyl-3,4,11,11a-tetrahydro-
2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11b, 120 mg,
79%).
(13) Ethyl 2-(2-Bromoethyl)-5,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (9b)
A mixture of tetrahydroisoquinoline 7b (800 mg, 3.02
mmol), 1,2-dibromoethane (11.35 g, 60.4 mmol), and
K2CO3 (417 mg, 3.02 mmol) was stirred at reflux for 24 h.
Then, the mixture was poured onto H2O and exhaustively
extracted with EtOAc. The combined organic phases were
washed with sat. NaHCO3, dried (MgSO4), filtered, and
evaporated in vacuo. Purification chromatography on silica
(hexane–EtOAc) gave pure ethyl 2-(2-bromoethyl)-5,8-
dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(9b, 786 mg,70%).
Analytical Data
1H NMR (270 MHz, CDCl3): δ = 0.91 (3 H, t, J = 7.3 Hz,
Me), 1.55–1.64 (2 H, m, CH2-2′), 2.59–2.69 (2 H, m, H-11a,
H-3a), 2.96 (1 H, dd, J = 3.9, 11.5 Hz, H-12), 3.09–3.29 (4
H, m, H-3b, H-4a, H-6a, H-1′a), 3.41–3.70 (3 H, m, H-4b, H-
1′b, H-11b), 3.74 (3 H, s, OMe), 3.76 (3 H, s, OMe), 4.10 (1
H, d, J = 15.5 Hz, H-6b), 6.61 (1 H, d, J = 8.1 Hz, H-8), 6.63
(1 H, d, J = 8.1 Hz, H-9). 13C NMR (68 MHz, CDCl3): δ =
11.2 (Me), 20.2 (C-2′), 27.6 (C-11), 46.1 (C-4), 48.4 (C-1′),
50.4 (C-3), 53.2 (C-6), 55.6 (OMe), 55.7 (OMe), 61.5 (C-
12), 107.1 and 107.7 (C-8, C-9), 123.4 and 124.7 (C-7a, C-
10a), 149.7 (=COMe), 151.5 (=COMe), 168.6 (C=O). IR
Analytical Data
1H NMR (300 MHz, CDCl3): δ = 1.23 (3 H, t, J = 7.0 Hz,
Me), 2.95 (1 H, dd, J = 6.3, 17.3 Hz, H-4a), 3.08–3.18 (2 H,
m, CH2-1′), 3.20 (1 H, dd, J = 6.1, 17.3 Hz, H-4b), 3.50 (2 H,
t, J = 7.2 Hz, CH2-2′), 3.75 (3 H, s, OMe), 3.76 (3 H, s,
OMe), 3.76 (1 H, dd, overlap, H-3), 3.85 (1 H, d, J = 16.8
Hz, H-1a), 3.96 (1 H,d, J = 16.8 Hz, H-1b), 4.07–4.18 (2 H,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 69–74

74
T. Nguyen Van et al.
LETTER
(NaCl): ν = 2931, 1654 (C=O), 1645, 1485, 1463, 1438,
1259, 1181, 1097 cm–1. MS: m/z (%) = 305 (100) [M + H+],
301 (10), 227 (20). HRMS (ES+): m/z calcd for
[C17H25N2O3]+: 305.1865; found: 305.1871.
dimethoxy-2-propyl-1,2,3,4,6,11-hexahydropyrazino[1,2-
b]isoquinoline-11a-carbonitrile (13a, 26 mg, 84%).
Analytical Data
White powder; mp 128.5–129.3 °C. 1H NMR (300 MHz,
CDCl3): δ = 0.94 (3 H, t, J = 7.3 Hz, CH3-3), 1.52–1.57 (2 H,
m, 2 × H-2′), 2.11 (1 H, d, J = 11.3 Hz, H-1a), 2.27–2.38 (3
H, m, overlap, H-3a, H-1′a, H-1′b), 2.63–2.71 (2 H, m,
overlap, H-11a, H-4a), 2.84–2.91 (2 H, m, overlap, H-3b, H-
4b), 3.12 (1 H, d, J = 17.0 Hz, H-11b), 3.21 (1 H, d, J = 11.3
Hz, H-1b), 3.28 (1 H, d, J = 16.8 Hz, H-6a), 3.76 (3 H, s,
OMe), 3.78 (3 H, s, OMe), 4.00 (1 H, J = 16.8 Hz, H-6b),
6.63 (2 H, s, H-9, H-8). 13C NMR (75 MHz, CDCl3): δ = 11.7
(Me), 19.8 (C-2′), 32.3 (C-11), 49.1 (C-6), 51.5 (C-4), 52.7
(C-3), 55.5 (2 × OMe), 56.7 (C-11a), 59.5 (C-1′), 61.7 (C-1),
107.5 and 107.6 (C-7, C-8), 117.5 (CN), 119.9 and 122.7
(C7a, C-10a), 149.6 (=COMe), 150.7 (=COMe). IR (KBr): ν
= 2931, 2835, 2183 (CN), 1652, 1607, 1486, 1463, 1456,
1259, 1172, 1080 cm–1. MS: m/z (%) = 316 (15) [M + H+],
301 (15), 290 (25), 289 (100). HRMS (ES+): m/z calcd for
[C18H26N3O2]+: 316.2025; found: 316.2025.
(16) 7,10-Dimethoxy-2-propyl-1,3,4,6,11,11a-hexahydro-2H-
pyrazino[1,2-b]isoquinoline (14a)
To a solution of 7,10-dimethoxy-2-propyl-3,4,11,11a-
tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11b,
100 mg, 0.33 mmol) in anhydrous Et2O (5 mL) under a
nitrogen atmosphere at 0 °C, was added LiAlH4 (53 mg, 1.32
mmol) portionwise. The reaction mixture was stirred for 12
h at r.t. Afterwards, the mixture was poured onto H2O and
exhaustively extracted with Et2O. The combined organic
phases were washed, dried (MgSO4), filtered, and
evaporated in vacuo. Purification by chromatography on
silica (hexane–EtOAc) gave pure 7,10-dimethoxy-2-propyl-
1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline
(14a, 76 mg, 80%).
Analytical Data
Pale white solid; mp 105 °C. 1H NMR (270 MHz, CDCl3): δ
= 0.92 (3 H, t, J = 7.3 Hz, CH3), 1.50–1.59 (2 H, m, CH2-2′),
1.93 (1 H, dd, J = 9.7, 11.0 Hz, H-1a), 2.21–2.36 (3 H, m,
overlap, H-3a, H-1′a, H-1′b), 2.41–2.53 (2 H, m, overlap, H-
11a, H-4a), 2.79 (1 H, d, J = 14.2 Hz, H-11b), 2.95 (1 H, dd,
J = 2.3, 11 Hz, H-1b), 3.01–3.09 (2 H, m, H-3b, H-4b), 3.13
(1 H, d, J = 16.0 Hz, H-6a), 3.77 (6 H, s, 2 × OMe), 4.06 (1
H, d, J = 16.0 Hz, H-6b), 6.62 (2 H, s, H-9, H-8). 13C NMR
(68 MHz, CDCl3): δ = 12.0 (Me), 20.0 (C-2′), 28.2 (C-11),
52.1 (C-6), 53.2 (C-4), 54.6 (C-3), 55.6 (2 × OMe), 60.1 (C-
1′), 60.7 (C-1), 76.6 (C-11a), 107.0 and 107.2 (C-8, C-9),
123.6 and 124.2 (C7a, C-10a), 149.8 (=COMe), 150.9
(=COMe). IR (ATR): ν = 2925, 1654, 1482, 1438, 1258,
1086, 1060, 810, 714 cm–1. MS: m/z (%) = 291 (100) [M +
H+]. HRMS (ES+): m/z calcd for [C17H27N2O2]+: 291.2073;
found: 291.2065.
(18) 2-Benzyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-
b]isoquinoline-1,7,10-trione (12)
To a solution of 7,10-dimethoxy-2-benzyl-3,4,11,11a-
tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11d,
176 mg, 0.5 mmol) in anhydrous CH2Cl2 (20 mL) was added
dropwise BBr3 (1035 mg, 1.05 mmol) under a nitrogen
atmosphere at –78 °C. After 1 h, the reaction mixture was
warmed to 0 °C and left for 30 min. Then, HNO3 (10 M,
10 mL) was added to the reaction mixture and stirring was
continued for 45 min. Next, the mixture was poured onto
H2O, neutralised with a sat. aq NaHCO3 solution and
exhaustively extracted with CH2Cl2. The combined organic
phases were washed, dried (MgSO4), filtered, and
evaporated in vacuo. Purification by chromatography on
silica (hexane–EtOAc) gave pure 2-benzyl-3,4,11,11a-
tetrahydro-2H,6H-pyrazino[1,2-b]isoquinoline-1,7,10-
trione (12, 110 mg, 68%).
(17) 7,10-Dimethoxy-2-propyl-1,2,3,4,6,11-hexahydro-
pyrazino[1,2-b]isoquinoline-11a-carbonitrile (13a)
To a mixture of fresh LiAlH4 (40 mg, 1.0 mmol) in
anhydrous Et2O (5 mL) was added anhydrous EtOH (0.175
mL, 3.0 mmol) under a nitrogen atmosphere at 0 °C. After
90 min, a solution of 11a (30 mg, 0.1 mmol) in anhydrous
THF (5 mL) was added, and the reaction mixture was stirred
at 0 °C for 30–50 min. Next, AcOH (0.226 mL, 4 mmol) was
added. After 5 min, KCN (40 mg, 0.61 mmol) in H2O was
added dropwise (CAUTION: HCN formation!). The
reaction mixture was stirred for 5 h at r.t., then the mixture
was poured onto H2O, neutralised with sat. aq NaHCO3
solution and exhaustively extracted with EtOAc. The
combined organic phases were washed, dried (MgSO4),
filtered, and evaporated in vacuo. Purification by
Analytical Data
1H NMR (270 MHz, CDCl3): δ = 2.47–2.60 (1 H, m, H-11a),
2.64 (1 H, dt, J = 3.6, 12.3 Hz, H-3a), 3.02 (1 H, dd, J = 4.1,
10.6 Hz, H-12), 3.06–3.19 (3 H, m, overlap, H-4a, H-3b, H-
6a), 3.33 (1 H, td, J = 3.6, 19.8 Hz, H-4b), 3.49 (1 H, dt,
J = 4.1, 11.2 Hz, H-11b), 3.90 (1 H, dd, J = 1.3, 19.8 Hz, H-
6b), 4.53 (1 H, d, J = 14.5 Hz, H-1′a), 4.73 (1 H, d, J = 14.5
Hz, H-1′b), 6.71 (1 H, d, J = 10.2 Hz, H-8), 6.76 (1 H, d,
J = 10.2 Hz, H-9), 7.26–7.37 (5 H, m, 5 × =CH). 13C NMR
(68 MHz, CDCl3): δ = 26.4 (C-11), 45.2 (C-4), 49.8 (C-3),
49.9 (C-1′), 51.5 (C-6), 60.4 (C-12), 127.7 (=CH), 128.1
(2 × =CH), 128.7 (2 × =CH), 136.0 (C-8), 136.3 (Cquat),
136.5 (C-9), 138.6 (Cquat), 140.4 (Cquat), 167.4 (C=O), 185.7
(C=O), 185.9 (C=O). IR (NaCl): ν = 2924, 1660 (C=O),
1641 (C=O), 1496, 1453, 1352, 1311, 1250 cm–1. MS: m/z
(%) = 323 (5) [M + H+], 322 (20), 321 (100), 178 (7).
chromatography on silica (hexane–EtOAc) gave pure 7,10-
Synlett 2014, 25, 69–74
© Georg Thieme Verlag Stuttgart · New York

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