1,3-Dipolar cycloadditions from tricyclic hemiaminals. Synthesis of the quinocarcin core through catalyst-free generation of azomethine ylides

Article abstract of DOI:10.1039/c1ob05181d

The generation of azomethine ylides from the readily accessible hemiaminals 3 and 8 or from iminium salt 10 was studied. Compounds 8 gave anti- and syn-cycloadducts containing the quinocarcin core through a catalyst-free dehydration process.

Full text of DOI:10.1039/c1ob05181d

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PAPER
1,3-Dipolar cycloadditions from tricyclic hemiaminals. Synthesis of the
quinocarcin core through catalyst-free generation of azomethine ylides†
Lena Huck, J. Francisco Gonza´lez, Elena de la Cuesta, J. Carlos Mene´ndez and Carmen Avendan˜o*
Received 1st February 2011, Accepted 8th June 2011
DOI: 10.1039/c1ob05181d
The generation of azomethine ylides from the readily accessible hemiaminals 3 and 8 or from iminium
salt 10 was studied. Compounds 8 gave anti- and syn-cycloadducts containing the quinocarcin core
through a catalyst-free dehydration process.
Introduction
1,3-Dipolar cycloaddition (1,3-DPC) reactions using azomethine
ylides as 1,3-dipolar reactive intermediates are powerful tools for
the synthesis of substituted pyrrolidine rings. Common methods
for the in situ generation of these unstable species are: a)
proton abstraction or decarboxylation in imino derivatives of a-
amino acids promoted by Lewis acids, bases, organocatalysts, or
dehydrating agents; b) thermolysis or photolysis of aziridines; and
c) dehydrohalogenation or desilylation of iminium salts.1–5 Other
compounds, such as N-methoxymethylaminomethyl trimethylsi-
lanes are azomethine ylide equivalents.6
Tetrahydroisoquinoline antitumour antibiotics7,8 exhibit a
piperazine moiety and a bicyclic isoquinoline framework where
the benzene ring may be a phenol, a hydroquinone, or a quinone.
This skeleton, which is common to the whole group, is fused to a
pyrrolidine at positions 1–3 in the quinocarcin subfamily. Archety-
pal members of this subfamily are quinocarcin and its synthetic
aminonitrile analogue DX-52-1, lemonomycin, and cyanocycline
A (Fig. 1). Quinocarcin is also known as quinocarmycin and its
more stable citrate salt as KW2152. Most of these compounds
have shown an interesting antineoplastic activity,9–11 and several
synthetic approaches to them have been reported.12–14
Fig. 1 Examples of natural and synthetic members of the quinocarcin
and naphthyridinomycin subfamilies.
In the last years we have developed a simple and effi-
cient method to achieve the preparation of tetrahydropyrazino
[1,2-b]isoquinoline-1,4-diones,15 which were used as building
Results and discussion
Hemiaminals 3 were obtained by the chemoselective reduction
of the C-1 carbonyl group in compounds 2, that were derived
from compounds 1 according to previously reported procedures
(Scheme 1).15,19 Unfortunately, we found that these hemiaminals
were not suitable for the generation of azomethine ylides of type
A through water elimination because of competitive reactions.
For instance, attempts to condense compound 3a with acrolein
through the generation of ylide A, obtained by thermal dehy-
dration, did not give the desired cycloadduct, affording instead
enamide 4. A similar result was obtained when the generation of
ylide A was attempted from 3c, giving enamides 5 and 6 through
a two-step dehydration mechanism.
blocks in the synthesis of compounds with the saframycin
subfamily skeleton.16,17 The key step to afford the pentacyclic
system was the partial reduction of the C(1)-carbonyl group to give
hemiaminal intermediates, which were precursors of the iminium
species involved in Pictet–Spengler type cyclizations.18 We study
here the dehydration of these hemiaminals to give azomethine
ylides and their use to efficiently synthesize the quinocarcin core
through 1,3-DPC reactions.
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia,
Universidad Complutense, Plaza Ramo´n y Cajal s/n, 28040 Madrid, Spain.
E-mail: avendano@farm.ucm.es
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. See DOI: 10.1039/c1ob05181d
These results moved us to explore alternative 1,3-DPC reactions
involving 11,11a-unsaturated hemiaminals 8a, 8b and 8d and
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Scheme 1 Synthesis and reactivity of saturated hemiaminals 3.
Table 1 Assayed experimental conditions of 1,3-DPC reactions with
hemiaminals 8
iminium salt 10. Compounds 8 were obtained from 2 by a
bromination–dehydrohalogenation reaction tandem with NBS
and AIBN in CCl4, followed by treatment of enamides 7 with
LiAlH(OtBu)3 (Scheme 2). Hydrolytic N-deprotection of 8a gave
9, which was converted to the iminium salt 10 by reaction
with iodomethane in refluxing methanol. The attempted 1,3-
DPC reaction between 10 and diethyl acetylenedicarboxylate in
the presence of Et3N was expected to afford a cycloadduct of
azomethine ylide B (compound 11) but instead gave a complex
mixture from which the only isolated product seemed to arise
from the generation of azomethine ylide C by a mechanism
involving an initial proton abstraction at the exocyclic methyl
group as suggested by 1H–13C NMR correlation studies, although
this compound could not be isolated in a pure state. We reasoned
that 1,3-DPC reactions starting from hemiaminals 8, lacking the
exocyclic methyl substituent, should not suffer from this problem.
Gratifyingly, this expectation was borne out by experiment and,
furthermore, we found that the generation of the azomethine ylides
D from 8 does not require addition of any catalyst, since it proceeds
through spontaneous dehydration in refluxing toluene.
The reactions of 8 with activated alkenes or alkynes gave the
exo adducts 12–20 or their dehydro analogues 21–25, respectively.
The anti-isomers, which resulted from the approach of the
dipolarophile from the least hindered face of the azomethine ylide,
were the major products in most cases and, not unexpectedly
and, a higher bulk of the R6 substituent in 8b and 8d improves
this selectivity (Scheme 3). We obtained the best results when
reactions were carried out at 120 ◦C in a sealed tube, although
for dipolarophiles with a high boiling point such as acrylonitrile
or DEAD the reactions can be performed under standard reflux
conditions.
Entry
1
Compounds
anti/syn ratio
Overall yield (%)
12 and 13
7/3
60a
62b
54c
11a
54b
70b
70b
51
2
14 and 15
6/4
3
4
5
6
7
8
16
1/0
8/2
10/3
6/4
1/1
1/0
17 and 18
19 and 20
21 and 22
23 and 24
25
52b
58b
23b
a Reflux conditions. b Sealed tube. c Microwave.
isomer relationship whether the reactions were done in a sealed
tube or MW irradiation conditions was always in the same order
as when the reaction was performed in reflux conditions (Table 1).
The stereochemical assignment of anti and syn isomers was
based on a correlation between the H-6 proton and CH proton of
the isopropyl group in an NOE experiment for the syn isomer.
The exo configuration for the R1 group in compounds 12–20
was established based on the NOE effect between H-1 and H-
12 protons and H-11 and H-12. This diastereoselection, giving
compounds with the quinocarcin configuration as the minor prod-
ucts, is in accordance with the findings of Williams’s group in the
total syntheses of ( )-quinocarcinamide and (-)-tetrazomine.20,21
In this work analogues of azomethine ylides D were generated
through the NBS-mediated oxidation of tetrahydropyrazino[1,2-
b]isoquinoline-4-ones followed by base-promoted deprotonation
with simultaneous bromide elimination. The structural study of
compounds 12–24 (and also of some of their precursors) was
The use of microwave irradiation decreased the reaction time, as
compared to conventional heating, but gave similar yields, and the
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Scheme 2 Synthesis of iminium salt 10 and 1,3-DPC reactions.
Scheme 3 1,3-DPC reactions with unsaturated hemiaminals 8.
◦
complicated by the presence of the carbamate group. Carbamates
usually contain significant populations of rotamers,22 leading to
decrease of the temperature to 15 C leads to clearly duplicated
peaks, and this effect is even clearer at 5 ◦C. These findings
confirm the existence of rotamers, and rule out the existence of
diastereoisomers in compound 18 (see Supporting Information).
In conclusion, we have developed a new synthetic strategy
that permits highly functionalized cycloadducts to be obtained
from readily accessible hemiaminals 8 through a catalyst-free
dehydration process.
1
the presence of two or more sets of peaks in H and 13C NMR
spectra of pure samples at ambient temperature. To demonstrate
the presence of rotamers in our samples, we have studied the effect
1
of temperature on the H-NMR spectrum of compound 18 in
◦
CDCl3. We have observed that at 40 C, only one set of signals
was observed, even though some of them were rather broad. A
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1). Anal. calcd. for C16H18N2O6: C, 57.48; H, 5.43; N, 8.38. Found:
C, 57.05; H, 5.12; N, 7.98%.
Experimental
General experimental
General procedure for the synthesis of compounds 2a–c
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions
were monitored by thin layer chromatography, on aluminium
plates coated with silica gel with fluorescent indicator (SDS
CCM221254). Separations by flash chromatography were per-
formed on silica gel (SDS 60 ACC 40–63 mm). Melting points
were measured on a Reichert 723 hot stage microscope, and are
uncorrected. Infrared spectra were recorded on a Perkin Elmer
Paragon 1000 FT-IR spectrophotometer, with all compounds
examined as KBr pellets or as thin films on NaCl disks. NMR
spectra were obtained on a Bruker Avance-250 spectrometer
operating at 250 MHz for 1H and 63 MHz for 13C (CAI de
Resonancia Magne´tica Nuclear, Universidad Complutense) or a
Bruker AC-500 spectrometer (500 MHz for 1H and 125 MHz for
13C) for the case of compound 13. For compounds comprising
mixtures of rotamers, only the data for major species are given.
In some cases, the carbonyl group of the carbamate moiety
gives very broad signals that are difficult to distinguish from the
background,23 but can be easily detected in the infrared spectrum.
High resolution mass measurements were performed by the CAI
de Espectrometria de Masas, Universidad Complutense, using an
FTMS Bruker APEX QIV instrument. Elemental analyses were
determined by the CAI de Microana´lisis Elemental, Universidad
Complutense, using a Leco 932 CHNS combustion microanalyzer.
A solution of compound 1 (9.1 mmol), triethylamine (54 mmol)
and 4-dimethylaminopyridine (27 mmol) in dry DCM (140 mL)
was cooled in ice water, and isopropyl chloroformate (18 mmol)
was added dropwise. The solution was stirred under argon
atmosphere for 16 h at room temperature and then, water
(50 mL) was added. After extraction with DCM (20 mL ¥ 3), the
extracts were washed with HCl (25 mL ¥ 3), H2O (30 mL) and with
saturated aqueous solution of NaCl (30 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo to give a residue that
was purified by flash column chromatography on silica gel.
(6S*,11aS*)-Methyl 2-isopropoxycarbonyl-7,10-dimethoxy-1,4-
dioxo-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinoline-6-
carboxylate (2b). The residue was purified by flash column
chromatography on silica gel with hexane/ethyl acetate (7 : 3) as
eluent to give 2b (95%) as a white solid. Mp 164–165 ◦C; IR
nmax (film): 2981, 1921, 1628 and 1501 cm-1; 1H NMR (250 MHz,
CDCl3) d: 6.82 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.48
(s, 1H), 5.13 (sept, J = 6.2 Hz, 1H), 4.66 (dd, J = 7.9 and 6.3 Hz,
1H), 4.54 (d, J = 17.2 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 3.82 (s,
6H), 3.76 (s, 3H), 3.31 (dd, J = 17.0 and 7.9 Hz, 1H), 3.20 (dd,
J = 17.0 and 6.3 Hz, 1H), 1.37 (d, J = 6.2 Hz, 1H); 13C NMR (63
MHz, CDCl3) d: 169.5, 165.7, 163.3, 151.0, 150.7, 150.1, 122.4,
120.6, 110.2, 108.9, 72.5, 55.9, 54.8, 52.9, 50.6, 47.8, 24.5, 21.6.
HRMS (negative ESI), m/z: Calcd for C20H24N2O8: 420.15327
(M+). Found: 419.14599 (M+ - 1). Anal. calcd. for C20H24N2O8: C,
57.14; H, 5.75; N, 6.66. Found: C, 56.85; H, 5.48; N, 6.21%.
One-pot synthesis of compounds 1
To
a stirred solution of 1-acetyl-3-(2,5-dimethoxybenzyl)-
piperazine-2,5-dione (3.26 mmol) in dry DCM (50 mL) were added
TMSCl (4.9 mmol) and triethylamine (4.9 mmol) and the mixture
was stirred under an argon atmosphere at room temperature for
1 h. Then, the corresponding dimethyl acetal (6.52 mmol) and
TMSOTf (9.78 mmol) were added and this mixture was stirred
for 12 h at room temperature or for an additional 48 h at reflux
conditions (for compound 1b). The reaction was quenched with
a 10% aqueous solution of NaHCO3 (50 mL) and extracted with
DCM (30 mL¥3). The combined extracts were washed with H2O
(20 mL) and with a saturated aqueous solution of NaCl (20 mL),
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo,
to give a residue that was purified by flash column chromatography
on silica gel.
(6R*,11aS*)-2-Isopropoxycarbonyl-7,10-dimethoxy-6-naphthy-
lcarbonyloxymethyl-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]iso-
quinoline-1,4-dione (2d). To a solution of 2c (400 mg, 0.83 mmol)
was added Pd/C (66 mg) in ethanol (4 mL) and the mix-
ture was stirred under hydrogen atmosphere (3 atm), at
70 ◦C, for 3.5 h. Then, the mixture was filtered through celite
and the solvent was concentrated in vacuo to give an oil residue.
The unpurified crude was used in the next step. A solution of this
crude, EDC (2.3 mmol), 4-dimethylaminopyridine (1.21 mmol)
and naphthoic acid (1.2 mmol) in dry DCM (20 mL) was stirred
under argon atmosphere for 20 h at room temperature. Then the
solvent was evaporated and the residue was dissolved in AcOEt
(150 mL), the organic solution was washed with HCl 0.1 N (50
mL), NaHCO3 (50 mL), H2O (30 mL) and a saturated aqueous
solution of NaCl (30 mL), dried over anhydrous Na2SO4, filtered
and concentrated in vacuo to give a residue that was purified
by flash column chromatography on silica gel with hexane/ethyl
acetate mixture (8 : 2) as eluent to give 2d as a brown oil (265 mg,
44%). IR nmax (film): 2981, 1780, 1509 cm-1; 1H NMR (250 MHz,
CDCl3) d: 8.80 (d, J = 7.9 Hz, 1H), 8.19 (dd, J = 7.3 and 1.1 Hz,
1H), 8.04 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 7.3 and 1.7 Hz, 1H),
7.54 (m, 3H), 6.79 (m, 2H), 6.34 (dd, J = 9.0 and 3.3 Hz, 1H), 5.07
(sept, J = 6.2 Hz, 1H), 4.91 (dd, J = 11.6 and 9.0 Hz, 1H), 4.80
(dd, J = 11.4 and 5.0 Hz, 1H), 4.69 (dd, J = 11.6 and 3.3 Hz, 1H),
4.41 (d, J = 17.8 Hz, 1H), 4.29 (d, J = 17.8 Hz, 1H), 3.88 (s, 3H),
3.83 (s, 3H), 3.52 (dd, J = 17.3 and 5.0 Hz, 1H), 2.95 (dd, J = 17.3
and 11.4 Hz, 1H), 1.33 (d, J = 6.2 Hz, 6H); 13C NMR (63 MHz,
(6S*,11aS*)-Methyl 7,10-dimethoxy-1,4-dioxo-1,2,3,4,11,11a-
hexahydro - 6H - pyrazino[1,2 - b]isoquinoline - 6 - carboxylate
(1b). Purification by flash chromatography on silica gel with
methanol/dichloromethane (1 : 9) as eluent gave 1b (54%) as a
yellow solid. Mp 160–161 ◦C; IR nmax (film): 1661, 1628 and 1563
cm-1; 1H NMR (250 MHz, CDCl3) d: 6.74 (d, J = 8.8 Hz, 1H), 6.69
(d, J = 8.8 Hz, 1H), 6.45 (s, 1H), 6.08 (ws, 1H), 4.43 (dd, J = 11.7
and 4.6 Hz, 1H), 4.17 (d, J = 16.5 Hz, 1H), 4.07 (d, J = 16.5 Hz,
1H), 3.76 (s, 6H), 3.72 (s, 3H), 3.42 (dd, J = 17.5 and 4.6 Hz, 1H),
2.80 (dd, J = 17.5 and 11.7 Hz, 1H); 13C NMR (63 MHz, CDCl3)
d: 169.5, 167.2, 161.9, 150.9, 150.4, 122.6, 120.1, 109.6, 108.4,
55.8, 55.7, 53.0, 52.9, 51.3, 44.8, 27.4. HRMS (negative ESI), m/z:
Calcd for C16H18N2O6: 334.11649 (M+). Found: 333.10921 (M+ -
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CDCl3) d: 167.2, 165.8, 162.5, 151.1, 151.0, 149.9, 133.7, 133.6,
131.3, 130.6, 128.5, 127.8, 126.4, 126.2, 125.6, 124.6, 122.9, 120.6,
109.4, 108.4, 72.4, 63.1, 55.7, 55.6, 53.5, 48.4, 47.6, 27.2, 21.6.
HRMS (negative ESI), m/z: Calcd for C30H30N2O8: 546.20022
(M+). Found: 545.19305 (M+ - 1). Anal. calcd. for C30H30N2O8 C,
65.92; H, 5.53; N, 5.13; Found: C, 65.50; H, 5.46; N, 5.22%.
was concentrated to dryness in vacuo. The residue was dissolved
in anhydrous DCM (3 mL) and cooled in ice water. After addition
of acrolein (0.4 mL, 6 mmol) and Et3N (0.42 mL, 3 mmol) the
mixture was stirred at room temperature for 3.5 h and extracted
with AcOEt (20 mL ¥ 2). The extracts were washed with NH4Cl
(30 mL), H2O (30 mL) and a saturated aqueous solution of NaCl
(30 mL), dried over anhydrous Na2SO4, filtered and concentrated
in vacuo to give a residue, that was purified by flash column
chromatography on silica gel with hexane/ethyl acetate (7 : 3) as
eluent to give 5 as an orange solid (25%) and 6 as a yellow solid
(43%).
General procedure for the synthesis of hemiaminals 3 and 8
To a stirred solution of lithium tri-tert-butoxyaluminum hydride
(8.12 mmol) in dry THF (50 mL) cooled in ice water was added
a solution of compounds 2 or 7 (2.7 mmol) in dry THF, and the
mixture was stirred under argon atmosphere at room temperature
for 16 h. The reaction mixture was quenched by addition of ice,
filtered over celite, and extracted with ethyl acetate. The organic
phases were washed with H2O and with a saturated aqueous
solution of NaCl, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo.
6-Benzyloxymethyl-2-isopropoxycarbonyl-7,10-dimethoxy-2,3,
6,11 - tetrahydropyrazino[1,2 - b]isoquinoline - 4 - one (5). Mp 64–
65 ◦C; IR nmax(film): 2980, 1649 and 1599 cm-1; H NMR (300
1
MHz, CDCl3) d: 7.19 (m, 5H), 6.63 (d, J = 7.5 Hz, 1H), 6.59 (d,
J = 7.5 Hz, 1H), 6.31 (dd, J = 7.0 and 3.0 1H), 6.12 (ws, 0.7H),
6.00 (ws, 0.3H), 4.84 (sept, J = 6.5 Hz, 1H), 4.62 (d, J = 12.0 Hz,
1H), 4.45 (m, 2H), 4.33 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 18.6 Hz,
1H), 3.89 (m, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.37 (dd, J = 10.8
and 3.3 Hz, 1H), 1.17 (m, 6H). 13C NMR (85 MHz, CDCl3) d:
164.6, 154.4, 149.6, 148.6, 138.6, 128.4, 127.9, 127.6, 120.9, 118.8,
116.2, 110.4, 109.7, 102.4, 72.5, 69.6, 68.9, 55.8, 55.5, 47.9, 46.6,
35.9, 21.8. HRMS (negative ESI), m/z: Calcd for C26H30N2O6:
466.21039 (M+). Found: 489.19961 (M+ + Na). Anal. calcd. for
C26H30N2O6: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.71; H, 6.23;
N, 5.84%.
(1R*,6R*,11aS* and 1S*,6R*,11aS*)-1-Hydroxy-2-isopro-
poxycarbonyl-7,10-dimethoxy-6-methyl-1,2,3,6,11,11a-hexahydro-
pyrazino[1,2-b]isoquinolin-4-one (3a). According to the general
procedure compound 3a (86%) was obtained as a crude product
in a 7/3 diasteroisomer mixture. IR nmax (film): 3325, 2979, 1704
and 1634 cm-1; 1H NMR (250 MHz, CDCl3) d: 6.67 (s, 2H), 5.93
(q, J = 6.4 Hz, 1H), 5.84 (ws, 1H), 4.93 (sept, J = 6.1 Hz, 1H), 4.34
(m, 1H), 4.30 (d, J = 17.5 Hz, 0.3H), 4.02 (m, 2H), 3.78 (s, 4.2H),
3.76 (s, 1.8 H), 3.20 (dd, J = 17.2 and 8.0 Hz, 0.3H), 2.96 (dd, J =
17.2 and 7.5 Hz, 1H), 2.49 (m, 1H), 1.52 (d, J = 7.2, 2.1H), 1.40
(d, J = 6.5, 1.3H), 1.31 (d, J = 6.5, 6H), 1.27 (m, 6H), 1.20 (d, J =
6.0, 1.3H); 13C NMR (63 MHz, CDCl3) d: 176.8, 165.2, 163.0,
150.8, 150.3, 149.8, 149.2, 127.7, 126.5, 122.3, 121.5, 107.8, 107.7,
107.6, 76.3, 76.2, 70.1, 70.0, 55.5, 55.4, 52.6, 50.8, 44.8, 44.1, 43.9,
43.4, 23.8, 21.8, 18.9, 18.3. HRMS (negative ESI), m/z: Calcd for
C19H26N2O6: 378.17909 (M+). Found: 377.17181 (M+ - 1).
6-Benzyloxymethyl-2-isopropoxycarbonyl-7,10-dimethoxy-1,2,
3,6◦- tetrahydropyrazino[1,2 - b]isoquinolin - 4 - one (6). Mp 64–
1
65 C; IR nmax (film): 2934, 1649 and 1452 cm-1; H NMR (250
MHz, CDCl3) d: 7.23–7.00 (m, 5H), 6.41 (m, 2H), 6.26 (m, 1H),
6.13 (ws, 0.7H), 6.00 (ws, 0.3H), 4.85 (sept, J = 5.2 Hz, 1H), 4.63 (d,
J = 11.9 Hz, 1H), 4.51 (m, 1H), 4.34 (d, J = 11.9 Hz, 1H), 4.08 (d,
J = 12.3 Hz, 1H), 3.92 (m, 2H), 3.64 (s, 3H), 3.62 (s, 3H), 3.60 (m,
1H), 3.35 (m, 1H), 1.19 (m, 6H); 13C NMR (63 MHz, CDCl3) d:
164.3, 154.1, 150.5, 148.4, 140.5, 138.4, 138.2, 133.7, 128.8, 128.5,
128.3, 127.8, 127.7, 127.6, 127.3, 126.2, 119.2, 112.5, 111.7, 72.8,
69.7, 69.5, 62.1, 55.8, 55.6, 48.2, 47.2, 35.9, 31.6, 22.7, 22.2. Anal.
calcd. for C26H30N2O6: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.61;
H, 6.19; N, 5.79%.
2-Isopropoxycarbonyl-7,10-dimethoxy-6-methyl-1,2,3,6-
tetrahydropyrazino[1,2-b]isoquinolin-4-one (4)
Compound 3a (0.26 mmol) was dissolved in toluene (5 mL) and
acrylonitrile (5 eq) was added. The reaction was carried out in
◦
a sealed tube for 48 h at 120 C. Then the solvent was removed
General procedure for compounds 7
in vacuo and the residue was purified by column chromatography
on silica gel with hexane/ethyl acetate (7 : 3) as eluent to give the
compound 4 (32%) as a yellow oil. IR nmax (film): 2979, 1702 and
A solution of 2a, 2b or 2d (6.9 mmol), AIBN (0.69 mmol) and
NBS (8.3 mmol) in CCl4 (70 mL) was refluxed under an argon
atmosphere for 16 h. The unreacted NBS was filtered from the
cooled reaction, the solvent was evaporated under reduced pres-
sure, and the residue was purified by flash column chromatography
on silica gel. Characterization data for one representative example
are given here. For full data, see the Supporting Information.
1
1648 cm-1; H NMR (250 MHz, CDCl3) d: 6.71 (s, 2H), 6.23
(ws, 1H), 6.05 (q, J = 6.5 Hz, 1H), 4.95 (sept, J = 6.4 Hz, 1H),
4.71 (m, 1H), 4.54 (d, J = 18.4 Hz, 1H), 4.11 (d, J = 18.4 Hz,
1H), 3.96 (m, 1H), 3.81 (s, 6H), 1.28 (m, 3H), 1.27 (m, 6H); 13C
NMR (63 MHz, CDCl3) d: 163.4, 154.0, 148.8, 148.2, 128.8, 123.1,
119.1, 109.7, 109.5, 101.3, 69.7, 55.9, 55.6, 48.3, 44.4, 22.1, 18.8.
HRMS (negative ESI), m/z: Calcd for C19H24N2O5: 360.16852
(M+). Found: 383.15774 (M+ + Na). Anal. calcd. for C19H24N2O5:
C, 63.32; H, 6.71; N, 7.77. Found: C, 63.03; H, 6.42; N, 7.35%.
2-Isopropoxycarbonyl-7,10-dimethoxy-6-naphtycarbonyloxy-
methyl-2,3-dihydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (7d).
IR nmax (film): 2360, 1717, 1489 cm-1; 1H NMR (250 MHz, CDCl3)
d: 8.88 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 7.2, 1H), 8.04 (d, J = 8.0 Hz,
1H), 7.89 (d, J = 7.4, 1H), 7.69 (s, 1H), 7.57 (m, 3H), 6.93 (d, J =
8.9, 1H), 6.84 (d, J = 8.9, 1H), 6.65 (dd, J = 7.8 and 3.5 Hz, 1H),
5.10 (sept, J = 6.2 Hz, 1H), 4.76 (d, J = 17.3 Hz, 1H), 4.58 (dd,
J = 11.4 and 7.8 Hz, 1H), 4.41 (dd, J = 11.4 and 3.5 Hz, 1H),
4.16 (d, J = 17.3 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 1.33 (m,
Synthesis of 5 and 6
To a solution of compound 3c (140 mg, 0.3 mmol) in anhydrous
DCM (3 mL) was added TFA (1.16 mL, 15 mmol). The reaction
was stirred for 3.5 h at room temperature and, then the reaction
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6H); 13C NMR (63 MHz, CDCl3) d: 166.9, 162.8, 158.9, 151.6,
150.2, 149.3, 133.7, 133.6, 133.5, 131.4, 130.8, 128.4, 127.7, 126.1,
125.8, 125.7, 124.6, 119.7, 119.0, 114.5, 113.0, 111.0, 72.3, 63.6,
56.0, 55.8, 47.6, 47.5, 21.6. HRMS (negative ESI), m/z: Calcd for
C30H28N2O8: 544.18457 (M+). Found: 543.17958 (M+ - 1). Anal.
calcd. for C30H28N2O8: C, 66.17; H, 5.18; N, 5.14. Found: C, 66.50;
H, 5.46; N, 5.24%.
(1S*,3R*,12S*,6S*)-13-Isopropoxycarbonyl-7,10-dimethoxy-6-
methyl-1,2,3,4,6,12-hexahydro-3,12-iminoazepino[1,2-b]isoquino-
line-1-carbonitrile (12). IR nmax (film): 3369, 2981, 1713 and
1
1692 cm-1; H NMR (250 MHz, CDCl3) d: 6.72 (s, 2H), 6.21 (s,
1H), 6.00 (q, J = 6.4 Hz, 1H), 5.23 (s, 1H), 5.00 (sept, J = 6.1 Hz,
1H), 4.81 (d, J = 5.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.09 (dd, J =
9.2 and 4.0, 1H), 2.59 (m, 1H), 2.45 (m, 1H), 1.30 (d, J = 6.1 Hz,
6H), 1.23 (d, J = 6.4 Hz, 3H); 13C NMR (63 MHz, CDCl3) d:
167.6, 154.2, 148.9, 148.1, 147.6, 132.4, 122.6, 120.1, 119.0, 109.9,
109.6, 100.5, 70.6, 61.3, 59.5, 55.9, 55.6, 44.5, 35.3, 34.0, 21.9, 19.1.
HRMS (negative ESI), m/z: Calcd for C22H25N3O5: 411.17942
(M+). Found: 410.17214 (M+ -1). Anal. Calcd for C22H25N3O5: C,
64.22; H, 6.12; N, 10.21. Found: C, 64.18; H, 6.06; N, 10.15%.
7,10-Dimethoxy-6-methyl-3,6-dihydropyrazino[1,2-b]isoquinolin-
4-one (9)
A solution of compound 8a (100 mg, 0.26 mmol) in 5 mL of a
mixture of TFA/H2SO4 (20 : 1) was stirred at room temperature
for 16 h. Then the mixture was dropped over a saturated aqueous
solution of NaHCO3. The aqueous residue was extracted with
dichloromethane (20 mL ¥ 3) and the organic extracts were washed
with H2O and with a saturated aqueous solution of NaCl, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to
give the unstable imine 9 (60 mg, 85%) as a brown oil. 1H NMR
(250 MHz, CDCl3) d: 7.99 (ws, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.74
(d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 6.10 (q, J = 6.5 Hz, 1H), 4.69
(d, J = 23.2 Hz, 1H), 4.40 (d, J = 23.2 Hz, 1H), 3.86 (s, 3H), 3.83
(s, 3H), 1.28 (d, J = 6.5 Hz, 3H); 13C NMR (63 MHz, CDCl3) d:
164.1, 155.4, 149.2, 148.9, 127.6, 124.3, 118.7, 111.8, 109.5, 108.2,
108.6, 56.0, 55.7, 44.0, 24.0, 19.7.
(1S*,3S*,12R*,6S*)-13-Isopropoxycarbonyl-7,10-dimethoxy-6-
methyl-1,2,3,4,6,12-hexahydro-3,12-iminoazepino[1,2-b]isoquino-
line-1-carbonitrile (13). IR nmax
and 1489 cm-1; 1H NMR (250 MHz, CDCl3)
d: 6.72 (s, 2H), 6.25 (s, 1H), 5.88 (q,
(film): 3279, 1713
J
=
6.3 Hz, 1H), 5.19 (s, 1H), 4.95 (sept, J = 6.3 Hz, 1H), 4.84
(m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.20 (m, 1H), 2.63 (m, 2H),
1.28 (m, 6H), 1.23 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d: 165.3, 148.8, 148.6, 130.9, 122.7, 120.0, 118.5, 110.3,
109.8, 100.8, 77.1, 70.5, 59.9, 56.0, 55.7, 44.2, 32.6, 21.9, 18.5.
HRMS (negative ESI), m/z: Calcd for C22H25N3O5: 411.17942
(M+). Found: 410.17214 (M+ -1). Anal. Calcd for C22H25N3O5: C,
64.22; H, 6.12; N, 10.21. Found: C, 64.02; H, 5.87; N, 9.96%.
7,10-Dimethoxy-2,6-dimethyl-4-oxo-3,4-dihydro-6H-pyrazino[1,2-
b]isoquinolinium iodide (10)
Acknowledgements
To a solution of unpurified compound 9 in anhydrous methanol
(5 mL), methyl iodide (0.03 mL, 0.44 mmol) was added and the
mixture was stirred at reflux for 2 h. Then the solvent was removed
in vacuo to give 10 (50 mg, 94%) as a green oil. IR nmax (film): 2933,
This work was supported by MICINN (grant CTQ2009-
12320/BQU), and Universidad Complutense de Madrid (CCG07-
UCM-2882). A Rafael Folch fellowship to Lena Huck is also
acknowledged.
1
1575, 1489 and 1261 cm-1; H NMR (250 MHz, CDCl3) d: 8.06
(s, 1H), 7.40 (s, 1H), 6.80 (m, 2H), 6.37 (q, J = 6.7 Hz, 1H), 4.33
(d, J = 19.2 Hz, 1H), 3.82 (m, 9H), 3.71 (d, J = 19.2 Hz, 1H),
1.52 (d, J = 6.7 Hz, 3H); 13C NMR (63 MHz, CDCl3) d: 156.1,
149.7, 149.1, 145.6, 137.2, 126.3, 122.6, 120.2, 109.8, 108.9, 55.9,
46.6, 24.1, 18.5. Anal. Calcd for C16H19IN2O3: C, 46.39; H, 4.62;
N, 6.76. Found: C, 46.23; H, 4.26; N, 6.45%.
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This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6271–6277 | 6277
©