Synthesis of two unnatural oxygenated aaptaminoids

Article abstract of DOI:10.1021/jo3020598

Two unprecedented oxygenated aaptaminoids have been synthesized starting from cheap and easily available 2,3-dihydroxybenzoic acid with the satisfactory overall yields of 31% and 34%. The key step of the procedure is the divergent thermic 5-exodig vs base

Full text of DOI:10.1021/jo3020598

Note
pubs.acs.org/joc
Synthesis of Two Unnatural Oxygenated Aaptaminoids
Giorgio Abbiati,*,† Arjana Doda,† Monica Dell’Acqua,† Valentina Pirovano,† Diego Facoetti,†
Silvia Rizzato,‡ and Elisabetta Rossi†
†Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A. Marchesini”, Universita
̀
degli Studi di Milano,
via Venezian, 21, 20133 Milano, Italy
‡Dipartimento di Chimica, Universita
̀
degli Studi di Milano, via Golgi, 19, 20133 Milano, Italy
S
* Supporting Information
ABSTRACT: Two unprecedented oxygenated aaptaminoids
have been synthesized starting from cheap and easily available
2,3-dihydroxybenzoic acid with the satisfactory overall yields of
31% and 34%. The key step of the procedure is the divergent
thermic 5-exodig vs base-promoted 6-endodig cyclization of a 5-
alkynylquinolinone derivative.
aptamine1 I is the ancestor of a series of natural alkaloids
known as “aaptamines” and characterized by the presence
of a benzo[de][1,6]naphthyridine ring in their framework
(Figure 1). All aaptamines have been isolated from marine
Aaptamines show a broad range of pharmacological activities
such as antioxidant and scavenger of free radicals, enzymatic
inhibitor, antiviral, antimicrobial, and antifungal agents,
cytotoxic agent, and antagonist of some receptors. In particular,
the ancestor aaptamine I shows in vitro a significant antioxidant
activity4 (albeit slightly lower than those of isoaaptamine III
and demethylaaptamine IV, Figure 1), a moderate antifungal
activity toward Candida tropicalis,5 and an interesting cytotoxic
activity toward cancer cells.1,6 It is an especially effective
competitive α-adrenoceptor antagonist endowed with potential
cardiotonic effects.7
A
A number of total syntheses of aaptamine have been
reported,1,8 involving two conceptually different approaches
for the construction of the benzo[de][1,6]naphthyridine ring
(Figure 2): the synthesis of a new pyridine ring fused with a
preformed isoquinoline scaffold (AB)9 or fused with a
quinoline skeleton (AC).10
Figure 1. Main members of the family of tricyclic aaptamines.
Figure 2. Disconnections in reported total synthesis of aaptamine I.
sponges of the class Demospongiae (also called “horny sponges”
or “siliceous sponges”), the largest class in the phylum Porifera.
In particular, sponges of genus Aaptos are the most important
producers of aaptamines.
Aaptamine I was isolated for the first time in 1981 by the
Nakamura group2 from the sponge Aaptos aaptos (Schmidt,
1864) collected off the Okinawa island coast. Five years later,
the same group isolated from the same kind of sponge (A.
aaptos) two congeners, the 9-demethylaaptamine IV and the
demethyloxyaaptamine VI3 (Figure 1). Over the following
years aaptamine I and its congeners have been found in many
other horny sponges collected from the Indian Ocean and the
Red Sea, off the coasts of Australia, Indonesia, and Malaysia,
from the Caribbean Sea, and off the Brazilian coast.
For several years, we have been interested in the develop-
ment of domino strategies11 for the synthesis of nitrogen-
containing heterocycles12 starting from alkynes.13 Many efforts
have been devoted to the synthesis of nitrogen-containing rings
by tandem imination/annulation of γ- or δ-ketoalkynes in the
presence of ammonia.14,15 In particular, a series of substituted
isoquinolines have been recently obtained by microwave-
enhanced domino reactions of o-alkynylbenzaldehydes16 and o-
alkynylacetophenones17 (the latter, with the aid of silver
Received: September 19, 2012
Published: October 22, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Quinolinone 7 and the First Attempt to Key Intermediate 8
Scheme 3. Synthesis of Oxygenated Aaptaminoid 11
catalysis). The approach was also successfully transformed into
a multicomponent process starting from simple o-bromoben-
zaldehyde, terminal alkynes, and ammonia.18 Bearing in mind
the strategies reported in the literature, we were intrigued to
verify the possibility to apply our domino approach to the
isoquinoline nucleus as a key step for a new total synthesis of
aaptamine I. Thus, we planned a retrosynthetic analysis
(Scheme 1) that involves our imination/cyclization sequence
on a properly substituted 5-ethynylquinolin-4(1H)-one as final
key-step. The 5-ethynylquinolin-4(1H)-one seemed to be easily
obtainable by a classical Sonogashira coupling between the
corresponding 5-haloquinolin-4(1H)-one and a terminal
alkyne. Substituted quinolinone could be prepared by the
Valderrama’s synthesis starting from properly functionalized
aniline, in turn obtainable through a Curtius−Yamada
rearrangement starting from the suitable substituted benzoic
acid synthesized from cheap and available 2,3-dihydroxybenzoic
acid by a simple aromatic halogenation and O-methylation
reactions (Scheme 1).
Once the key intermediates were identified, we performed
the synthesis (Scheme 2). By treating 2,3-dihydroxybenzoic
acid with bromine in acetic acid at room temperature for 24 h,
the 5-bromo-2,3-dihydroxybenzoic acid, 2, was selectively
obtained in almost quantitative yield.19 The hydroxyl groups
of 2 were efficiently methylated by reaction with dimethyl
sulfate in acetone and potassium carbonate followed by basic
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Scheme 4. Synthesis of Oxygenated Aaptaminoid 14
Scheme 5. Proposed Mechanism for the Formation of Aaptaminoid 14
hydrolysis of methyl ester and acidification to give the 5-bromo-
2,3-dimethoxybenzoic acid, 3.19 The synthesis of 3 through this
double step was necessary because the direct bromination of
the simple and readily available 2,3-dimethoxybenzoic acid led
to the formation of a mixture of 4- and 5-bromo-derivatives.
The acid 3 was transformed into the amine 5 via a Curtius−
Yamada reaction20 in two steps; the treatment of 3 with
diphenylphosphoryl azide in a mixture of ethanol and THF at
65 °C for 2 h gave the carbamate 4 which was immediately
hydrolyzed by treatment with KOH in ethanol at reflux to give
the amine 5 in excellent yield.21
The 5-bromoquinolinone 7 was obtained in two steps
following the Valderrama’s protocol.22 The bromoaniline 5 was
reacted with trimethyl orthoformate and Meldrum’s acid to give
the intermediate 6 in quantitative yield; next, the 5-
bromoquinolinone 7 was obtained by brief heating of 6 in
diphenylether at 260 °C with good yield. Unexpectedly, despite
a number of different reaction conditions having been tested,
any attempt to obtain the key intermediate 8 by a Sonogashira
cross-coupling reaction failed (Scheme 2).
To overcome this drawback, we decided to introduce the
triple bond in an earlier step of the synthesis (Scheme 3).
Hence, bromoaniline 5 was reacted with trimethylsilylacetylene
under classical Sonogashira23 conditions to quickly give
alkynylaniline 9 in very good yield. The treatment of 9 with
trimethyl orthoformate and Meldrum’s acid at 100 °C for 3 h
gave the intermediate 10 in 93% yield.19 Surprisingly, the
heating of 10 at 260 °C for 10 min did not provide the
expected 5-alkynylquinolinone 8 but gave directly the tricyclic
compound 11, via a sequential double cyclization, namely the
synthesis of quinolinone 8 as a non-isolable intermediate,
followed by the thermally promoted 5-exodig cycloisomeriza-
tion (Scheme 3). The structure24 of the new oxygenated
aaptaminoid 11 was assigned on the basis of NMR and MS
data, and confirmed by X-ray diffractometric analysis.
These results prompted us to try an alternative approach to
alkynylquinolinone 8. We were persuaded that the failure of the
alkynylation of 5-bromoquinolinone, 7, was somewhat related
to the presence of a secondary enaminone system, inside the
bicyclic ring, that behaves like an interfering amide vinylog.
Consequently, we tried to protect the nitrogen of the
quinolinone (Scheme 4). Nevertheless, all attempts to protect
the nitrogen with di-tert-butyl dicarbonate25 and p-toluene-
sulfonyl chloride inexplicably failed, whereas the treatment of 7
with sodium hydride and benzyl chloroformate26 in THF gave,
unexpectedly, the O-protected 5-bromo-4-hydroxyquinoline
derivative, 12, in good yield.27 As hypothesized, after the
deactivation of the enaminone system, the Sonogashira reaction
between compound 12 and trimethylsilylacetylene took place
and gave the alkynylated product 13 in good yield. The latter
was easily deprotected by hydrogenolysis with 1,4-cyclo-
hexadiene and Pd/C28 to give the key intermediate 8 in good
yield. However, the reaction of 8 with ammonia in methanol,
already at rt, gave the new oxygenated aaptaminoid 14 in 85%
yield. Furthermore, the direct reaction of 13 with ammonia in
methanol at 120 °C under microwave heating for 1 h gave the
aaptaminoid 14 in even better yield (Scheme 4). The
structure29 of 14 was assigned on the basis of NMR and MS
data and confirmed by the X-ray diffractometric analysis.
The straightforward formation of pyrano[2,3,4-de]quinoline,
14, also starting directly from Cbz-protected compound 13,
could be explained as follows. The deprotection of benzylox-
ycarbonyl-protected phenolic oxygens by bases,30 also in
alcoholic medium,31 is a well-known procedure, and even the
system ammonia/methanol was yet successfully used.31c
Moreover, ammonia and methanol are able to remove the
silyl group from the key intermediate 832 and to promote the
subsequent 6-endodig cycloisomerization, even at room temper-
ature; the driving force in the final step is the formation of
pyrano[2,3,4-de]quinoline, 14, a compound strongly stabilized
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Note
by resonance (Scheme 5). This sequence is in agreement with
related literature findings.33
at reduced pressure to give 2,3-dimethoxy-5-bromobenzoic
acid, 3 (3.57 g, 91%), as white solid. The product was
sufficiently pure to be used in the next step without further
purification. Mp 104−105 °C (lit. 199−200 (EtOAc/hexane),19
122−124 (H2O)34). 1H NMR (CDCl3, 200 MHz): δ = 3.93 (s,
3H), 4.07 (s, 3H), 7.25 (d, 1H, J = 2.4), 7.86 (d, 1H, J = 2.4),
11.12 (brs, 1H). 13C NMR (CDCl3, 50.3 MHz): δ = 56.6, 62.5,
117.6, 120.8, 123.9, 126.5, 147.9, 153.2, 164.8. MS (ESI+): m/z
(%) = 283/285 (65, M+ + Na), 261/263 (100, MH+), 243/245
(83, MH+ − H2O).
Ethyl-(5-bromo-2,3-dimethoxyphenyl)carbamate, 4. To a
solution of 2,3-dimethoxy-5-bromobenzoic acid, 3 (3.00 g,
11.49 mmol), in dry THF (40 mL) were added diphenylphos-
phoryl azide (3.32 g, 2.60 mL, 12.06 mmol), absolute ethanol
(6.55 mL, 115 mmol), and anhyd TEA (1.40 g, 1.91 mL, 13.79
mmol). The mixture was stirred at 65 °C for 2 h. A strong
evolution of gas was observed. After cooling to room
temperature, the reaction was concentrated under reduced
pressure, and the crude was dissolved with EtOAc (70 mL).
The organic phase was successively washed with saturated
aqueous NaHCO3 solution (60 mL), water (60 mL), and brine
(60 mL) and was dried over anhyd sodium sulfate and
concentrated at reduced pressure. The reaction crude was
purified by flash column chromatography on silica gel (eluent:
hexane/EtOAc = 95:5) to give ethyl-(5-bromo-2,3-
dimethoxyphenyl)carbamate, 4 (2.90 g, 83%), as a pale-yellow
oil. 1H NMR (CDCl3, 200 MHz): δ = 1.33 (t, 3H, J = 7.1), 3.83
(s, 3H), 3.85 (s, 3H), 4.24 (q, 2H, J = 7.1), 6.75 (d, 1H, J =
2.2), 7.24 (brs, 1H), 7.98 (d, 1H, J = 2.2). 13C NMR (CDCl3,
50.3 MHz): δ = 14.7, 56.3, 60.9, 61.6, 110.5, 114.2, 117.1,
133.3, 136.3, 152.6, 153.4. MS (ESI+): m/z (%) = 326/328
(100, M+ + Na), 304/306 (36, MH+), 258/260 (31, MH+ −
C2H6O). Anal. Calcd (%) for C11H14BrNO4 (304.14): C 43.44,
H 4.64, N 4.61. Found: C 43.27, H 4.69, N 4.57.
5-Bromo-2,3-dimethoxyaniline, 5. To a solution of ethyl
(5-bromo-2,3-dimethoxyphenyl)carbamate, 4 (1.64 g, 5.39
mmol), in ethanol (10 mL), was added a solution of potassium
hydroxide (3.18 g, 56.6 mmol) in ethanol (16 mL). The
mixture was refluxed for 15 h, cooled to room temperature and
concentrated under reduced pressure. The residue was diluted
with EtOAc (15 mL), washed with brine (15 mL), dried over
anhyd sodium sulfate, and concentrated at reduced pressure.
The reaction crude was purified by flash column chromatog-
raphy on silica gel (eluent: hexane/EtOAc = 90:10) to give 5-
bromo-2,3-dimethoxyaniline, 5 (1.2 g, 96%), as yellow solid.
Mp 59−61 °C. 1H NMR (CDCl3, 200 MHz): δ = 3.78 (s, 3H),
3.82 (s, 3H), 3.87 (brs, 2H), 6.45 (d, 1H, J = 2.2), 6.53 (d, 1H,
J = 2.2). 13C NMR (CDCl3, 50.3 MHz): δ = 56.2, 60.0, 106.3,
111.8, 116.9, 135.3, 141.9, 153.7. MS (ESI+): m/z (%) = 232/
234 (100, MH+), 217/219 (10, MH+ − CH3). Anal. Calcd (%)
for C8H10BrNO2 (232.07): C 41.40, H 4.34, N 6.04. Found: C
41.52, H 4.39, N 5.98.
5-[(5-Bromo-2,3-dimethoxyphenylamino)methylene]-2,2-
dimethyl-1,3-dioxane-4,6-dione, 6. 2,2-Dimethyl-1,3-dioxane-
4,6-dione (Meldrum’s acid) (0.635 g, 4.39 mmol) and trimethyl
orthoformate (15 mL) were refluxed for 2 h. Then a solution of
5-bromo-2,3-dimethoxyaniline, (5 1.00 g, 4.31 mmol), in
trimethyl orthoformate (15 mL) was added dropwise, and
the reaction mixture was refluxed further for 3 h. The solvent
was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (eluent:
hexane/EtOAc = from 80:20 to 70:30) to give the Meldrum’s
acid derivative 6 (1.63 g, 98%) as a pale-yellow solid. Mp 165−
In conclusion, during the study for a new total synthesis of
aaptamine I two unnatural oxygenated aaptaminoids, 11 and
14, have been serendipitously discovered. The syntheses took
place in five and seven steps, respectively, with the satisfactory
overall yields of 31% and 34%, respectively. The common
starting material is the cheap and easily available 2,3-
dihydroxybenzoic acid. The key steps for the formation of
the oxygenated tricycles 11 and 14 are the divergent thermic 5-
exodig vs base-promoted 6-endodig cyclizations of 5-alkynylqui-
nolinone 8. The biological proprieties of the new aaptaminoids
11 and 14 will be evaluated.
EXPERIMENTAL SECTION
■
General Experimental Methods. All chemicals and
solvents are commercially available and were used without
further purification. Microwave-assisted reactions were per-
formed with a MILESTONE microSYNT multimode labsta-
tion, using 12 mL sealed glass vessels. The internal temperature
was detected with a fiber-optic sensor. All reactions were
performed at least twice. Silica on TLC Alu Foils F254 (Fluka)
were employed for thin layer chromatography (TLC). Silica gel
40−63 μm (SDS - Carlo Erba Reagents) was employed for
flash column chromatography. Melting points are uncorrected.
Unless otherwise specified, proton NMR spectra were recorded
at room temperature in CDCl3, at 200 or 300 MHz. Unless
otherwise specified, 13C NMR spectra were recorded at room
temperature in CDCl3 at 50.3 or 75.45 MHz. The APT
sequence was used to distinguish the methine and methyl
carbon signals from those due to methylene and quaternary
carbons. All 13C NMR spectra were recorded with complete
proton decoupling.
2,3-Dihydroxy-5-bromobenzoic Acid,19 2. To a solution of
2,3-dihydroxybenzoic acid (2.50 g, 16.22 mmol) in acetic acid
(20 mL) was dropwise added bromine (2.59 g, 0.83 mL, 16.22
mmol). The mixture was stirred at room temperature
overnight. The solvent was removed in vacuo to give a solid
which was dissolved in EtOAc (30 mL) and washed with brine
(2 × 20 mL). The organic layer was dried over anhyd sodium
sulfate and the solvent removed at reduced pressure to give 2,3-
dihydroxy-5-bromobenzoic acid, 2 (3.75 g, 99%), as a pale-pink
solid. The product was sufficiently pure to be used in the next
step without further purification. Mp 218−221 °C (lit. 203−
204 (EtOAc/hexane)19 222−223 (H2O)34). 1H NMR (DMSO,
200 MHz): δ = 7.10 (d, 1H, J = 2.3), 7.30 (d, 1H, J = 2.3), 9.89
(brs, 1H) (2 phenolic OH obscured). 13C NMR (DMSO, 50.3
MHz): δ = 109.7, 115.4, 122.3, 123.3, 148.3, 150.7, 171.7. MS
(ESI -): m/z (%) = 231/233 (58, MH−), 485/487 (100, dimer
+ Na).
2,3-Dimethoxy-5-bromobenzoic Acid,19 3. A mixture of
2,3-dihydroxy-5-bromobenzoic acid 2 (3.50 g, 15.02 mmol),
dimethyl sulfate (6.54 g, 51.88 mmol), potassium carbonate
(7.17 g, 51.88 mmol) in acetone (25 mL) was refluxed for 20 h.
The solid was filtered off on a sintered glass filter, and the
solution was concentrated to give a liquid which was dissolved
in methanol (25 mL), treated with NaOH (40% aq, 16 mL),
and refluxed for 2 h. The solvent was then removed under
reduced pressure, and the residue was dissolved in water (30
mL) and extracted with EtOAc (2 × 20 mL). The aqueous
phase was adjusted to pH <2 with HCl 37% aq (≅1.5 mL) and
extracted with EtOAc (3 × 15 mL). The organic layers were
dried over anhyd sodium sulfate, and the solvent was removed
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1
166 °C. H NMR (CDCl3, 200 MHz): δ = 1.75 (s, 6H), 3.89
163.7, 165.3. MS (ESI−): m/z (%) = 402 (100, MH−). Anal.
Calcd (%) for C20H25NO6Si (403.50): C 59.53, H 6.24, N 3.47.
Found: C 59.70, H 6.26, N 3.44.
(s, 3H), 3.94 (s, 3H), 6.90 (d, 1H, J = 2.0), 7.13 (d, 1H, J =
2.0), 8.58 (d, 1H, J = 14.4), 11.58 (bd, 1H, J = 14.4). 13C NMR
(CDCl3, 50.3 MHz): δ = 27.3, 56.6, 61.4, 88.6, 100.8, 105.4,
113.7, 117.4, 132.8, 138.5, 151.1, 154.0, 163.7, 165.3. MS
(ESI+): m/z (%) = 408/410 (69, MH+), 350/352 (70), 308/
310 (100). Anal. Calcd (%) for C15H16BrNO6 (386.20): C
46.65, H 4.18, N 3.63. Found: C 46.74, H 4.21, N 3.63.
5-Bromo-7,8-dimethoxyquinolin-4(1H)-one, 7. Meldrum’s
acid derivative 6 (1.5 g, 3.88 mmol) was refluxed in diphenyl
ether (10 mL) with a heating mantle. After 10 min the reaction
mixture was cooled and then purified by flash column
chromatography on silica gel eluting first with hexane (to
remove diphenyl ether) then sequentially with hexane/EtOAc
= 50:50, EtOAc, and finally EtOAc/MeOH = 98:2 to give 5-
bromo-7,8-dimethoxyquinolin-4(1H)-one, 7 (845 mg, 77%), as
(Z)-7,8-Dimethoxy-5-[(trimethylsilyl)methylene]-5H-furo-
[2,3,4-de]quinoline, 11. Meldrum’s acid derivative 10 (73 mg,
0.181 mmol) was refluxed in diphenyl ether (5 mL) with a
heating mantle. After 10 min the reaction mixture was cooled
and was purified by flash column chromatography on silica gel,
eluting first with hexane (to remove diphenyl ether), then with
hexane/EtOAc = 50:50 to give the tricyclic oxygenated
aaptaminoid 11 (28 mg, 51%) as an orange solid. Mp 89−91
°C. δ = 0.29 (s, 9H), 4.02 (s, 3H), 4.27 (s, 3H), 5.57 (s, 1H),
6.68 (d, 1H, J = 5.1), 7.33 (s, 1H) 8.73 (d, 1H, J = 5.1). 13C
NMR (CDCl3, 50.3 MHz): δ = −0.08, 57.8, 62.3, 97.7, 102.8,
106.4, 121.0, 125.9, 138.8, 144.4, 154.3, 155.6, 162.8, 163.6. MS
(ESI+): m/z (%) = 302 (100, MH+), 287 (15, MH+ − CH3).
Anal. Calcd (%) for C16H19NO3Si (301.41): C 63.76, H 6.35, N
4.65. Found: C 63.62, H 6.40, N 4.60.
1
light-brown solid. Mp 231−234 °C. H NMR (CDCl3, 200
MHz): δ = 3.97 (s, 3H), 3.98 (s, 3H), 6.18 (dd, 1H, J = 7.5, J =
1.7), 7.20 (s, 1H), 7.51 (dd, 1H, J = 7.5, J = 6.0), 8.74 (brs,
1H). 13C NMR (CDCl3, 75.45 MHz): δ = 56.8, 61.5, 111.9,
115.9, 116.3, 118.4, 134.9, 136.6, 152.3, 178.1 (one signal
obscured). MS (ESI+): m/z (%) = 306/308 (100, M+ + Na),
284 (23, MH+). Anal. Calcd (%) for C11H10BrNO3 (284.11): C
46.50, H 3.55, N 4.93. Found: C 46.41, H 3.60, N 4.99.
2,3-Dimethoxy-5-[(trimethylsilyl)ethynyl]aniline, 9. Under
a nitrogen atmosphere, to a solution of 5-bromo-2,3-
dimethoxyaniline, 5 (200 mg, 0,862 mmol), in anhyd
triethylamine (3.4 mL) were added trimethylsilylacetylene
(101 mg, 0.143 mL, 1.03 mmol) and PdCl2(PPh3)2 (98% w/w;
24.2 mg, 0.0344 mmol). The reaction was stirred at rt for 15
min, and then CuI (99% w/w; 3.1 mg, 0.0172 mmol) was
added. The reaction mixture was stirred at 70 °C for 12 h, until
no more starting product was detectable by TLC (eluent:
hexane/EtOAc = 70:30). The solvent was evaporated under
reduced pressure, and the crude material was purified by flash
column chromatography on silica gel (eluent: hexane/EtOAc =
90:10) to give 2,3-dimethoxy-5-((trimethylsilyl)ethynyl)aniline,
Benzyl-(5-bromo-7,8-dimethoxyquinolin-4-yl)carbonate,
12. To a suspension of NaH 55% mineral oil (160 mg, 3.66
mmol) in anhyd THF (10 mL) was added portionwise the
quinolinone 7 (400 mg, 1.41 mmol) at 0 °C. The mixture was
stirred for 30 min at 70 °C. Then, benzyl chloroformate (624
mg, 0.515 mL, 3.66 mmol) was slowly added dropwise. The
solution was allowed to cool to rt and stirred for 24 h. The
mixture was treated with aq 0.1 M HCl (50 mL) and extracted
with chloroform (3 × 30 mL). The combined organic layers
were dried over anhyd sodium sulfate and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent: hexane/EtOAc = 60:40)
to give benzyl-(5-bromo-7,8-dimethoxyquinolin-4-yl)carbonate,
1
12 (531 mg, 90%), as a pale-yellow solid. Mp 87−89 °C. H
NMR (CDCl3, 200 MHz): δ = 4.01 (s, 3H), 4.07 (s, 3H), 5.34
(s, 2H), 7.13 (d, 1H, J = 4.7), 7.37−7.47 (m, 5H), 7.63 (s, 1H),
8.92 (d, 1H, J = 4.7). 13C NMR (CDCl3, 50.3 MHz): δ = 57.3,
62.1, 71.3, 109.0, 114.0, 117.4, 122.9, 128.9, 129.2, 134.7, 143.5,
146.6, 151.5, 151.7, 152.9, 154.4 (one signal overlapped). MS
(ESI+): m/z (%) = 440/442 (78, M+ + Na), 418/420 (100,
MH+), 374/376 (18, MH+ − CO2). Anal. Calcd (%) for
C19H16BrNO5 (418.24): C 54.56, H 3.86, N 3.35. Found: C
54.59, H 3.88, N 3.32.
1
9 (194 mg, 91%), as an orange oil. H NMR (CDCl3, 200
MHz): δ = 0.23 (s, 9H), 3.81 (s, 3H), 3.82 (s, 3H), 3.82 (brs,
2H), 6.46 (d, 1H, J = 1.8), 6.53 (d, 1H, J = 1.8). 13C NMR
(CDCl3, 50.3 MHz): δ = 0.2, 56.0, 60.1, 92.5, 105.7, 106.7,
112.9, 118.7, 137.1, 140.6, 152.7. MS (ESI+): m/z (%) = 272
(19, M+ + Na), 250 (100, MH+), 178 (10, MH+ − Si(CH3)3).
Anal. Calcd (%) for C13H19NO2Si (249.39): C 62.61, H 7.68, N
5.62. Found: C 62.71, H 7.66, N 5.65.
Benzyl-[7,8-dimethoxy-5-((trimethylsilyl)ethynyl)quinolin-
4-yl]carbonate, 13. Under a nitrogen atmosphere, to a solution
of benzyl-(5-bromo-7,8-dimethoxyquinolin-4-yl)carbonate, 12
(142 mg, 0,340 mmol), in anhyd DMF (0.7 mL) were added
triethylamine (1.02 g, 1.4 mL, 10.04 mmol), trimethylsilylace-
tylene (40 mg, 0.056 mL, 0.408 mmol), and PdCl2(PPh3)2
(98% w/w; 9.5 mg, 0.014 mmol). The reaction was stirred at rt
for 15 min, and then CuI (99% w/w; 1.30 mg, 0.0068 mmol)
was added. The reaction mixture was stirred at 70 °C for 12 h
until no more starting material was detectable by TLC (eluent:
hexane/EtOAc = 20:80). The reaction crude was concentrated
under reduced pressure, and the residue was poured in water
(20 mL) and extracted with EtOAc (3 × 10 mL). The organic
layers were dried over anhyd sodium sulfate and concentrated
at reduced pressure. The reaction crude was purified by flash
column chromatography on silica gel (eluent: hexane/EtOAc =
60:40) to give benzyl [7,8-dimethoxy-5-[(trimethylsilyl)-
ethynyl]quinolin-4-yl]carbonate, 13 (109 mg, 74%), as a yellow
5-[(2,3-Dimethoxy-5-(trimethylsilylethynyl)phenylamino)-
methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione, 10. 2,2-Di-
methyl-1,3-dioxane-4,6-dione (Meldrum’s acid) (73 mg, 0.506
mmol) and trimethyl orthoformate (2.5 mL) were refluxed for
2 h. Then a solution of 2,3-dimethoxy-5-((trimethylsilyl)-
ethynyl)aniline 9 (75 mg, 0.301 mmol) in trimethyl
orthoformate (2.5 mL) was added dropwise, and the reaction
mixture was refluxed for 3 h until no more starting material was
detectable by TLC (eluent: hexane/EtOAc = 70:30). The
solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography on silica gel
(eluent: hexane/EtOAc = 90:10) to give the Meldrum’s acid
derivative 10 (112 mg, 93%) as a white solid. Mp 130−134 °C.
1H NMR (CDCl3, 200 MHz): δ = 0.26 (s, 9H), 1.74 (s, 6H),
3.88 (s, 3H), 3.97 (s, 3H), 6.86 (d, 1H, J = 1.6), 7.11 (d, 1H, J
= 1.6), 8.61 (d, 1H, J = 14.5), 11.55 (bd, 1H, J = 14.5). 13C
NMR (CDCl3, 50.3 MHz): δ = 0.04, 27.3, 56.4, 61.5, 88.3, 95.3,
103.7, 105.3, 111.5, 113.6, 119.8, 131.7, 139.8, 151.3, 153.0,
1
oil. H NMR (CDCl3, 200 MHz): δ = 0.23 (s, 9H), 4.03 (s,
3H), 4.11 (s, 3H), 5.31 (s, 2H), 7.09 (d, 1H, J = 4.8), 7.38 (m,
5H), 7.56 (s, 1H), 8.87 (d, 1H, J = 4.8). 13C NMR (CDCl3,
50.3 MHz): δ = 0.13, 57.1, 62.3, 71.1, 99.0, 103.5, 112.9, 113.0,
10465
dx.doi.org/10.1021/jo3020598 | J. Org. Chem. 2012, 77, 10461−10467

The Journal of Organic Chemistry
Note
119.0, 123.5, 128.6, 128.9, 129.0, 134.7, 144.6, 145.9, 151.3,
151.5, 152.6, 155.2. MS (ESI+): m/z (%) = 436 (100, MH+),
392 (45, MH+ − CO2). Anal. Calcd (%) for C24H25NO5Si
(435.55): C 66.18, H 5.79, N 3.22. Found: C 65.94, H 5.76, N
3.19.
non-hydrogen atoms. X-ray data as CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: giorgio.abbiati@unimi.it
■
7,8-Dimethoxy-5-[(trimethylsilyl)ethynyl]quinolin-4(1H)-
one, 8. In a screw capped test tube and under a nitrogen
atmosphere were added 1,4-cyclohexadiene (1.5 mL) and Pd/C
10% (74 mg, 100 wt %) to a solution of benzyl [7,8-dimethoxy-
5-[(trimethylsilyl)ethynyl]quinolin-4-yl]carbonate, 13 (74 mg,
0.170 mmol), in a mixture of EtOAc/EtOH = 1:1 (9.0 mL).
The reaction mixture was stirred at 50 °C for 2 h until no more
starting material was detectable by TLC (eluent: hexane/
EtOAc = 40:60). The solvents were removed under reduced
pressure, and the residue was purified by flash column
chromatography on silica gel (eluent: hexane/EtOAc =
60:40) to give 7,8-dimethoxy-5-((trimethylsilyl)ethynyl)-
quinolin-4(1H)-one, 8 (40 mg, 77%), as yellow wax. 1H
NMR (CDCl3, 200 MHz): δ = 0.29 (s, 9H), 3.97 (s, 3H), 4.00
(s, 3H), 6.17 (d, 1H, J = 7.5), 7.13 (s, 1H), 7.53 (dd, 1H, J =
7.5, J = 5.9), 8.90 (brs, 1H). 13C NMR (CDCl3, 50.3 MHz): δ =
0.20, 56.5, 61.4, 99.6, 104.9, 111.4, 116.7, 117.8, 121.9, 135.5,
135.6, 136.7, 151.7, 178.2. MS (ESI+): m/z (%) = 324 (34, M+
+ Na), 302 (100, MH+). Anal. Calcd (%) for C16H19NO3Si
(301.41): C 63.76, H 6.35, N 4.65. Found: C 63.85, H 6.39, N
4.64.
8,9-Dimethoxypyrano[2,3,4-de]quinoline 14. Method A. In
a screw-capped test tube and under a nitrogen atmosphere, a
solution of 7,8-dimethoxy-5-((trimethylsilyl)ethynyl)quinolin-
4(1H)-one, 8 (40 mg, 0.132 mmol), in dry ammonia in
methanol (NH3/MeOH 2 M solution, 2.5 mL) was stirred for 4
h at rt until no more starting material was detectable by TLC
(eluent: hexane/EtOAc = 50:50). The solvent was removed
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent: hexane/EtOAc =
60:40) to give 8,9-dimethoxypyrano[2,3,4-de]quinoline, 14 (26
mg, 85%), as yellow solid.
Method B. In a screw-capped glass vessel, a well-stirred
solution of benzyl-[7,8-dimethoxy-5-[(trimethylsilyl)ethynyl]-
quinolin-4-yl]carbonate, 13 (37 mg, 0.085 mmol), in dry
ammonia in methanol (NH3/MeOH 2 M solution, 2.5 mL)
was heated for 1 h at 120 °C in a multimode microwave oven
(ramp time not included = 10 min, max power = 400 W). The
reaction mixture was evaporated to dryness and the crude
purified by flash column chromatography on silica gel (eluent:
hexane/EtOAc = 60:40) to give 8,9-dimethoxypyrano[2,3,4-
de]quinoline, 14 (18 mg, 93%), as yellow solid. Mp 79−81 °C.
1H NMR (CDCl3, 200 MHz): δ = 3.97 (s, 3H), 4.02 (s, 3H),
6.20 (d, 1H, J = 5.9), 6.54 (d, 1H, J = 5.2), 6.68 (s, 1H), 6.85
(d, 1H, J = 5.9), 8.58 (d, 1H, J = 5.2). 13C NMR (CDCl3, 50.3
MHz): δ = 56.9, 61.2, 101.9, 104.4, 109.3, 115.8, 124.4, 140.7,
143.5, 145.6, 153.7, 154.1, 159.9. MS (ESI+): m/z (%) = 252
(36, M+ + Na), 230 (100, MH+), 215 (49, MH+ − CH3). Anal.
Calcd (%) for C13H11NO3 (229.23): C 68.11, H 4.84, N 6.11.
Found: C 67.95, H 4.88, N 6.05.
Notes
The authors declare no competing financial interest.
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■
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for compounds 2−14. A
full listing of crystallographic data for the structures of
compounds 11 and 14 including tables of bond distances and
bond angles. ORTEPIII figure of the independent molecule in
the asymmetric unit showing the numbering schemes for all
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10466
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