A domino Michael-Dieckmann-Peterson approach to the synthesis of substituted hydroxyquinolines and hydroxyisoquinolines

Article abstract of DOI:10.3184/030823410X12659067482702

A domino Michael-Dieckmann-Peterson approach to the synthesis of functionalised hydroxyquinolines and hydroxyisoquinolines is described.

Full text of DOI:10.3184/030823410X12659067482702

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 109
FEBRUARY, 109–113
A domino Michael–Dieckmann–Peterson approach to the synthesis of
substituted hydroxyquinolines and hydroxyisoquinolines
Biswajit Panda, Sankar Basak, Anindya Hazra and Tarun K. Sarkar*
Department of Chemistry, Indian Institute ofTechnology, Kharagpur-721302, India
A domino Michael–Dieckmann–Peterson approach to the synthesis of functionalised hydroxyquinolines and hydroxy-
isoquinolines is described.
Keywords: domino reaction, hydroxyquinolines, hydroxyisoquinolines, cis- β-silylacrylate
The common occurrence of quinoline and isoquinoline ring
systems in many alkaloids of biological significance has led
to the development of a large number of synthetic methods
for their construction.1–4 In particular, hydroxyquinoline and
hydroxyisoquinoline moieties are recognised as important
structural elements in many pharmacologically important
natural and non-natural products.5–11 Although a number of
synthetic routes have been developed for the synthesis of func-
tionalised hydroxyquinolines and hydroxyisoquinolines, it is a
significant challenge to explore a new approach for the synthe-
sis of this class of compounds. In this context we anticipated
that Michael–Dieckmann–Peterson type domino reaction
of azaphthalides 1 with a silyl-substituted conjugated olefin
2 would lead to substituted 8-hydroxyisoquinolines and 5-
hydroxyquinolines 5 via spontaneous Peterson elimination
from the cis-hydroxysilane 3 (Scheme 1). Besides there is a
possibility that trans-hydroxysilane 4 could be isolated, and
then this approach may also provide a route to the biologically
significant aza-arene metabolites featuring a trans-1,2-
diol functionality, e.g. 612–15 via steps including removal of
the electron withdrawing group (EWG) and silicon to oxygen
transformation (Tamao oxidation). We now report a novel
domino Michael–Dieckmann–Peterson route to 8-hydroxyiso-
quinolines and 5-hydroxyquinolines.16
afforded the desired azaphthalide 9 as a white crystalline solid
(m.p. 132–134 °C). The other azaphthalide 11 was prepared
by DIBAL-H mediated regioselective reduction of dimethyl 4,
6-dichloroquinolinate 10, prepared from ruthenium-catalysed
oxidative cleavage of 2,4-dichloroquinoline17 followed by
esterification (Scheme 3). Compound 11 was found to exist as
a white crystalline solid (m.p. 108–109 °C) and its structure
was confirmed by single crystal X-ray work (CCDC no
754876, Fig. 1).
With 9 and 11 in hand we first investigated the feasibility
of the domino Michael–Dieckmann reaction18–20 with simple
Michael acceptors like methyl acrylate. [To our knowledge the
potential of azaphthalides as partners in domino Michael–
Dieckmann reaction (also viewed as anionic [4+2] type cyclo-
addition) has not been investigated, see ref.19.] Addition of 1
equiv of LDA to 9 at –60 °C gave an orange coloured solution
of the lithiated azaphthalide which on exposure to methyl
acrylate gave adduct 12 as a white crystalline solid (m.p. 131–
133 °C) in 53% yield (Scheme 4). The structure of 12 was
1
confirmed from its H- and 13C NMR spectra. The adduct 12
was found to exist mainly (80%) in the enolic form, the rest
being a 1:1 mixture of the two keto diastereomers (cis/trans).
Further proof of the structure of 12 was obtained by conversion
into its diacetate derivative 14 (m.p. 88–90 °C) (Scheme 4).
Reaction of azaphthalide 11 with methyl acrylate under con-
ditions identical to those used for azaphthalide 9 followed
a similar pattern (enol: cis-keto: trans-keto = 8:1:1) and gave
adduct 13 (59%) (Scheme 5). We then examined the reaction
of azaphthalide 9 with phenyl vinyl sulfone; adduct 15 was
obtained as a 1:1 diastereomeric mixture. Here, however, no
enol form of the ketosulfone system was observed by NMR
Two different azaphthalides 9 and 11 were selected as test
substrates for our study. Azaphthalide 9 was prepared by base-
induced condensation of methyl 4-methoxyacetoacetate with
cyanoacetamide followed by treatment with POCl3 to give 7
(Scheme 2).
Subsequent reduction of 7 with diisobutylaluminum hydride
(DIBAL-H) followed by Pinnick oxidation of 8 cleanly
Scheme 1
* Correspondent. E-mail: tksr@chem.iitkgp.ernet.in

110 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2 (a) NCCH2CONH2, KOH, MeOH, reflux 8 h, 72%; (b) POCl3, 160–170 °C, 8 h, 65%; (c) DIBAL-H, CH2Cl2, –78 °C, 70%;
(d) NaClO2, NaH2PO4.2H2O, tBuOH-H2O, 0 °C→rt, 1h, rt, 12h, 78%.
spectroscopy. Incidentally, the sulfonyl group in 15 could be
reductively removed (SmI2/THF/ MeOH)21 to give 16 in 49%
yield (Scheme 4).
In order to achieve the synthesis of hydroxyquinolines
and hydroxyisoquinolines we then focused on the domino
Michael–Dieckmann–Peterson reaction of azaphthalides. For
this purpose, we prepared cis-β-silylacrylate 17 from acetylene
following the literature procedure.22 Treatment of azaphthalide
9 with 1 equiv of LDA at –60 °C and subsequent exposure
of the corresponding lithiated species to 17 gave the desired
substituted 8-hydroxyisoquinoline 18 (m.p. 169–171 °C) in
13% yield along with trans-adduct 19 (25%) in a ratio of 1:2,
respectively. The trans-adduct 19 could be converted into the
8-hydroxyisoquinoline 18 upon treatment with tetrabutylam-
monium fluoride in THF at ambient temperature (Scheme 6).
Interestingly, under similar conditions the other azaphthalide
11 gave only the domino Michael–Dieckmann–Peterson
product 20 (m.p. 115–117 °C) in 52% yield (Scheme 7); no
trans-adduct (cf. 4) was isolated from the crude reaction
mixture in this case. That the conversions of 9 to 18 and 11 to
20 do indeed proceed first via Michael reaction and then by
Dieckmann condensation followed by Peterson elimination
were established by some simple experiments. Thus, exposure
Scheme 3 (a) DIBAL-H, tol, –78˚C, 1h, −78 °C→rt, 2h, 84%.
Fig.1 ORTEP diagram of azaphthalide 11.
Scheme 4 (a) (i) LDA, THF, –60 °C (ii) CH =CHCO2Me, –60 °C→rt, 15 min, rt, 12h, 53%. (b) (i)LDA, THF, –60 °C; (ii) CH2=CHSO2Ph,
–60 °C→rt, 15 min, rt, 12h, 66%. (c) Ac22O, Et3N, DMAP (cat), CH2Cl2, 62%. (d) SmI2, THF, MeOH, –78 °C, 15 min, rt, 1h, 49%.
Scheme 5 (a) (i) LDA, THF, −60 °C (ii) CH2=CHCO2Me, −60 °C→rt, 15 min, rt, 12h, 59%.

JOURNAL OF CHEMICAL RESEARCH 2010 111
Scheme 6 (a) (i) LDA, THF, −60˚C; (ii) cis- MeO2CCH=CHSiMe (p-tol) (17), −60 °C→rt, 12h, 13% of 18 and 25% of 19
(b) Bu4NF, THF,2rt, 6 h.
Scheme 7 (a) (i) LDA, THF, −60 °C; (ii) cis- MeO2CCH=CHSiMe2(p-tol) (17), −60 °C→rt, 12h, 52%.
Scheme 8 (a) (i) LDA, THF, −60 °C; (ii) cis- MeO2CCH=CHSiMe2(p-tol) (17), −60 °C→rt, 2h, 11% of 21 with 16% of 19.
(b) LDA, THF, −60 °C→rt, 12h.
obtained and, where appropriate, purified before use unless specified
otherwise. Solvents were dried as follows: THF, toluene and Et2O
from sodium benzophenone ketyl; CH Cl2 from P O5 and Et N from
solid KOH. After drying, organic ex2tracts were2 evaporate3d under
reduced pressure and the residue was chromatographed on silica gel
(Rankem, 230-400 mesh) using EtOAc, petroleum ether (60–80 ˚C)
mixture as eluent. TLC was recorded using precoated plate (Merck,
silica gel 60 F254).
of lithiated 9 to 17 for a shorter duration allowed isolation of
diastereomerically pure Michael adduct 21 (m.p. 135–137 °C)
after chromatographic purification (Scheme 8). The stereo-
chemistry of 21 was confirmed by single crystal X-ray work.
(Detailed crystallographic data of compound 21 will be
published elsewhere.) As one would expect, exposure of 21
to LDA in THF led to the trans-adduct 19 obviously via the
Dieckmann condensation. Clearly, the other diastereomer of
19 undergoes straightforward Peterson elimination leading
to 18.
With a view to synthesising isoquinoline metabolites featur-
ing a trans-1,2-diol functionality, Tamao oxidation of 19 was
also carried out under various conditions.23 However, 19 was
found to be prone to Peterson elimination and gave 18 instead.
This difficulty may be overcome by replacing the p-
tolyldimethylsilyl group by a phenylsilacyclobutanyl24 group
which is known to undergo Tamao oxidation under extremely
mild conditions.
2,6-Dichloro-4-(chloromethyl)nicotinonitrile (7): To a stirred solu-
tion of cyanoacetamide (6.5 g, 77.4 mmol) in methanol (85 mL) was
added methyl 4-methoxyacetoacetate (10 mL, 77.4 mmol) dropwise
at room temperature. The resulting mixture, cloudy at first, was
warmed slightly to give a clear solution in about 5–10 min. Then a
solution of KOH (5.4 g, 95 mmol) in methanol (25 mL) was added
dropwise over a period of 1 h at ambient temperature. After some time
a white precipitate was formed and then the mixture was refluxed
for 8 h. After cooling to room temperature the resulting 3-cyano-2,6-
dihydroxy-4-methoxymethylpyridine monopotassium salt was fil-
tered. This salt was washed with methanol, dissolved in hot water
(in case of any undissolved material filtration was repeated) cooled
and acidified with conc. aq. HCl. Then the white solid product was
separated by filtration, washed with methanol, water and finally with
acetone. Drying of the solid mass in air afforded 2,6-dihydroxy-4-
(hydroxymethyl)nicotinonitrile (10.0 g, 72% yield). To each of the
four separate sealed tubes containing well-dried compound 2,6-
dihydroxy-4-(hydroxymethyl)nicotinonitrile (4.0 g, 22.22 mmol) was
added POCl3 (8.3 mL, 88.9 mmol) and then sealed. These tubes were
then heated at 160–170 °C for 8 h. Then the tubes were cooled to −20
°C, broken and the brown solution was carefully poured onto ice-cold
water. A deep brown gummy precipitate was formed which was fil-
tered and the residue was dissolved in methanol. It was then boiled
with activated charcoal, filtered, concentrated and purified by column
chromatography (silica gel, EtOAc/petroleum ether, 1:9) to give 7 as
yellowish oil (12.8 g, 65% yield). 1H NMR (200 MHz, CDCl3) δ 7.56
(s, 1H), 4.68 (s, 2H). 13C NMR (50 MHz, CDCl3) δ 154.6 (s), 154.2
(s), 152.9 (s), 123.0 (d), 112.0 (s), 108.6 (s), 41.1 (t). Anal. Calcd for
C7H Cl3N2: C, 37.96; H, 1.36; N, 12.64. Found: C, 38.23; H, 1.32; N,
12.539%.
In conclusion, a domino Michael–Dieckmann–Peterson
approach for the synthesis of hydroxyquinolines and hydroxy-
isoquinolines has been developed. Further detailed work on
hydroxyquinolines and -isoquinolines and the possibility of
achieving a novel route to aza-arene metabolites featuring
a trans-1,2-diol functionality are currently underway in our
laboratory.
Experimental
1
All melting points are uncorrected. H NMR and 13C NMR spectra
were recorded at ambient temperature at 500, 400 and 200 MHz and
125, 100 and 50 MHz, respectively. The data are reported as follows:
chemical shift in ppm from internal tetramethylsilane on the δ
scale, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), coupling constants (Hz), and integration.
Unless otherwise noted, all reactions were carried out under an inert
atmosphere in flame-dried flasks. All reagents were commercially

112 JOURNAL OF CHEMICAL RESEARCH 2010
2,6-Dichloro-4-(chloromethyl)nicotinaldehyde (8): To a stirred
solution of 3-cyano-2,6-dichloro-4-(chloromethyl)pyridine 7 (12.0 g,
54.6 mmol) in dichloromethane (300 mL) cooled to –78 °C was added
1.0 M solution of DIBAL-H in toluene (57 mL) dropwise. The result-
ing solution was then allowed to warm to ambient temperature and
stirred for another 2 h at the same temperature. It was then cooled to
0 °C and quenched with sat. aq. NH4Cl. This mixture was stirred for
1 h at 0 °C and then acidified with 1 M HCl. The organic layer was
separated, and the aqueous layer was extracted with CH Cl2 (3 × 20
mL). The combined organic fractions were washed wi2th saturated
aqueous solution of NaHCO3 and brine. The organic layer was dried
over Na2SO and concentrated under reduced pressure. The crude
residue was4 purified by flash chromatography (silica gel, EtOAc:
petroleum ether, 8:92) to give aldehyde 8 as a yellowish oil (8.3 g,
70% yield ). 1H NMR (200 MHz, CDCl3) δ 10.52 (s, 1H), 7.73 (s, 1H),
5.01 (s, 2H). 13C NMR (50 MHz, CDCl3) δ 190.4 (s), 154.9 (s), 154.5
(s), 152.9 (s, s), 124.3 (d), 42.3 (t).
injection over a period of 15 min. During the addition an initial orange
and finally orange-red colour was formed. After being stirred for
another 1h at –60 °C, methyl acrylate (0.1 mL, 1.17 mmol) diluted
with 2 mL THF was added dropwise, stirred at −60 °C for 15 min
and then the mixture was allowed to warm to room temperature. After
12 h stirring at room temperature it was quenched with saturated aque-
ous NH4Cl. The organic layer was separated and the aqueous layer
was extracted with diethyl ether. The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated. The crude product
was then purified by column chromatography (EtOAc: petroleum
ether, 40:60) to give 12 as a yellowish solid (150 mg, 53% yield).
M.p. 131–133 °C.1H NMR (200 MHz, CDCl ) δ 12.91 (s, 1H), 7.53
(s, 1H), 4.77 (dd, J = 12 Hz and 6.0 Hz, 1H),33.85 (s, 3H), 2.92 (dd,
J = 16 Hz and 6.0 Hz, 1H), 2.51 (dd, J = 16 Hz and 12.0 Hz, 1H)
(from enol tautomer); the signals of the cis/trans keto diastereomers
are at 7.67 (s, 1H), 7.57 (s, 1H) and 5.10 (dd, 1H), 4.94 (dd, 1H). 13
C
NMR (50 MHz, CDCl3) δ 172.53, 162.52, 156.82, 151.94, 147.81,
122.11, 119.55, 97.14, 67.47, 52.52, 29.38. Anal. Calcd or
C H Cl2NO4: C, 45.54; H, 3.13; N, 4.83. Found: C, 45.47; H, 3.09;
N1,14.982%.
4,6-Dichlorofuro[3,4-c]pyridin-3(1H)-one (9): To a 0 °C solution
of 2,6-dichloro-4-(chloromethyl)nicotinaldehyde 8 (3.5 g, 15.7 mmol)
in 16 mL tert-butyl alcohol were added NaClO2 (80%, technical,
4.6 g, 40.66 mmol) and NaH2PO4.2H2O (7.3 g, 47.14 mmol) in
11.9 mL of water over 25 min. The temperature was allowed to warm
to room temperature over 1 h. The reaction mixture was stirred at
room temperature for 12 h during which a white precipitate was
formed. The solid product was separated by filtration and washed with
cold water. Drying of the solid mass in vacuo afforded 9 (2.5 g, 78%
yield).
Methyl 2,4-dichloro-8-hydroxy-5-oxo-5,6,7,8-tetrahydroquinoline-
6-carboxylate (13): The experimental procedure for the preparation
13 was same as that described for the preparation of 12. From 2,4-
dichlorofuro[3,4-b]pyridin-5(7H)one 11 (200 mg, 0.98 mmol) was
obtained 13 (168 mg, 59% yield). 1H NMR (200 MHz, CDCl3) δ 12.84
(s, 1H), 7.35 (s, 1H), 4.72 (dd, J = 12 Hz and 8 Hz, 1H), 3.84 (s, 3H),
3.03 (dd, J = 16 Hz and 6 Hz, 1H), 2.42 (dd, J = 16 Hz and 12 Hz, 1H)
(from enol tautomer); the proton signals of the cis/trans keto diaste-
reomers are at 7.43 (s, 1H),7.42 (s, 1H) and 5.01 (dd, 1H), 4.85 (dd,
1H). 13C NMR (50 MHz, CDCl ) δ 172.67, 162.47, 162.24, 151.75,
144.24, 126.00, 121.25, 97.14, 637.57, 52.31, 27.60. MS: m/z (relative
intensity) 311.98 [(M+Na)+, 100]
M.p. 132–134 °C. 1H NMR (200 MHz, CDCl3) δ 7.43 (s, 1H), 5.27
(s, 2H). 13C NMR (50 MHz, CDCl3) δ 165.1 (s), 160.4 (s), 154.8 (s),
149.3 (s), 119.0 (s), 117.2 (d), 67.5 (t). MS: m/z (relative intensity)
203.90 [(M+H)+,100].Anal. Calcd for C7H3Cl NO2: C, 41.21; H, 1.48;
N, 6.87. Found: C, 41.27; H, 1.45; N, 6.92%.2
Methyl 5,8-diacetoxy-1,3-dichloro-5,6-dihydroisoquinoline-7-car-
boxylate (14): To a mixture of 12 (50 mg, 0.17 mmol), triethylamine
(0.12 mL, 0.86 mmol) and DMAP (cat.) in dichloromethane (1 mL)
was added acetic anhydride (0.1 mL, 0.88 mmol) under ice-cold con-
ditions. The mixture was stirred for 6 h at room temperature and then
it was quenched with H2O. The organic layer was separated and the
aqueous layer was extracted with diethyl ether. The combined organic
extracts were washed with water, brine, dried over anhydrous Na SO4
and concentrated. The crude product was then purified by col2umn
chromatography (EtOAc:petroleum ether, 40:60) to give 14 as a white
Dimethyl 4, 6-dichloroquinolinate (10): Ruthenium trichloride
hydrate (20 mg) was added to a mixture of sodium periodate (38.9 g,
181.8 mmol), acetonitrile (30 mL), carbon tetrachloride (30 mL),
water (45 mL) and the mixture was stirred for 30 min at room tem-
perature. To this was added 2,4-dichloroquinoline (3.0 g, 15.15 mmol)
in portions, and the reaction mixture was vigorously stirred for 48 h at
room temperature. The reaction mixture was filtered and the residue
was washed with hot ethyl acetate. From the combined filtrate the
organic layer was separated and the aqueous layer was extracted with
hot ethyl acetate. The combined organic layers were washed with
brine, dried (Na SO4) and evaporated to yield a crude oil. Without any
purification, the2crude oil was treated with an excess of ethereal diazo-
methane and stirred overnight in a fume hood. The reaction mixture
was concentrated under vacuum to give the title compound as a brown
gummy solid. The crude product was then purified by column chro-
matography (EtOAc: Petroleum ether, 1:9) to give 10 as white solid
1
crystalline solid (40 mg, 62% yield). M.p.88–90 °C. H NMR (400
MHz, CDCl ) δ 7.28 (s, 1H), 5.84 (dd, J = 8.8 Hz and 5.6 Hz,1H),
3.73 (s, 3H),32.95 (dd, J = 16.8 Hz and 5.6 Hz, 1H), 2.82 (dd, J = 17.0
Hz and 8.8 Hz,1H), 2.28 (s, 3H), 2.08 (s, 3H). 13C NMR (100 MHz,
CDCl ) δ 170.3 (s), 169.5 (s), 164.5 (s), 150.9 (s), 150.1 (s), 146.7 (s),
146.33(s), 122.9 (s), 120.9 (d), 118.1 (s), 67.0 (d), 52.4 (q), 28.7(t),
21.1 (q), 21.0 (q). Anal. Calcd for C H13Cl NO6: C, 48.15; H, 3.50;
N, 3.74. Found: C, 48.10; H, 3.39; N,153.82%2.
7-Benzenesulfonyl-1,3-dichloro-5-hydroxy-6,7-dihydro-5H-iso-
quinolin-8-one (15): The experimental procedure for the preparation
15 was same as that described for the preparation of 12 using phenyl
vinyl sulfone as a Michael acceptor instead of methyl acrylate. From
4,6-dichlorofuro[3,4-c]pyridin-3(1H)-one (9) (200 mg, 0.98 mmol)
was obtained 15 as a pale yellowish solid (240 mg, 66% yield). M.
p.164–166 °C. 1H NMR (200 MHz, DMSO-d6) δ 7.92–7.56 (m, 6H),
5.12–5.00 (m, 1H), 4.95–4.82 (m, 1H), 2.7–2.48 (m, 2H). 13C NMR
(50 MHz, DMSO-d ) δ 185.2 (s), 185.1 (s), 162.4 (s). 160.4 (s), 152.2
(s), 152.1 (s), 148.06(s), 147.6(s), 137.9 (s), 137.7 (s), 134.4 (d),134.2
(d), 129.3 (d), 129.3 (d), 128.7 (d), 128.6 (d), 123.8 (s), 123.4 (s),
121.8 (d), 119.7 (d), 67.45(d), 67.45(d), 63.8 (d), 62.9 (d), 30.7 (t),
29.7 (t). Anal. Calcd for C15H11Cl2NO4S: C, 48.40; H, 2.98;N, 3.76.
Found: C, 48.00; H, 2.90; N, 3.70%.
1,3-Dichloro-5-hydroxy-6,7-dihydro-5H-isoquinolin-8-one (16):
To a stirred blue solution of SmI2 (0.1 M solution of THF, 6.8 mL,
0.68 mmol) was added compound 15 (130 mg, 0.35 mmol) in THF
(2 mL) and MeOH (2mL) at –78 °C. The resultant brown mixture was
stirred for 15 min at −78 °C, warmed to room temperature and then
stirring was continued for 1 h at that temperature. Then it was poured
into a saturated aqueous solution of K CO3. The organic layer was
separated and the aqueous layer was ext2racted with diethyl ether. The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated. The crude product was then purified by column chroma-
tography (EtOAc:petroleum ether, 30:70) to give 16 as a yellowish oil
(40 mg, 49% yield). 1H NMR (200 MHz, CDCl3) δ 7.62 (s, 1H), 4.85
1
(3.3g, 82% yield). M.p. 135–137 °C, H NMR (200 MHz, CDCl3) δ
7.622 (s, 1H), 3.998 (s, 3H), 3.992 (s, 3H), 13C NMR (50 MHz, CDCl )
δ 164.4 (s), 163.0(s), 151.9(s), 146(s), 144.4(s), 130.6(s), 127.7(d3),
53.7(q), 53.4(q). MS: m/z (relative intensity) 264.14 [(M+H)+, 100].
2,4-Dichlorofuro[3,4-b]pyridin-5(7H)-one(11): To
a
stirred
solution of 10 (3.0 g, 11.36 mmol) in 100 ml of dry toluene cooled to
–78 °C was added 24 mL of DIBAL-H (1.0 M solution in toluene)
dropwise under argon atmosphere. The resulting mixture was stirred
for 1 h at the same temperature and then allowed to warm to room
temperature over 2 h. It was then cooled to 0 °C and quenched with
sat. aq. NH4Cl solution. This mixture was stirred for 1 h at 0 °C and
then acidified with 1 M HCl. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 × 5 mL). The combined
organic fractions were washed with saturated aqueous solution of
NaHCO3 and brine. The organic layer was dried over Na2SO4 and con-
centrated under reduced pressure. The crude residue was purified by
flash chromatography (silica gel, EtOAc: petroleum ether, 1:9) to give
azaphthalide 11 as a white crystalline solid (1.94g, 84% yield). M.p.
108–109 °C, 1H NMR (200 MHz, CDCl3) δ 7.50 (s, 1H), 5.27 (s, 2H),
13C NMR (100 MHz, CDCl3) δ 168.6 (s), 165.2(s), 157.9(s), 145.5(s),
125.5(d), 116.4(s), 69.1(t). MS: m/z (relative intensity) 203.95
[(M+H),+ 100].
Methyl 1,3-dichloro-5,8-dihydroxy-5,6-dihydroisoquinoline-7-car-
boxylate (12):To a stirred solution of LDA (0.98 mmol) [prepared
from 1.5 M n-BuLi in hexane (0.6 mL) and diisopropylamine
(0.16 mL, 1.17 mmol)] in THF (5 mL), cooled to–60 °C under argon
atmosphere was added slowly a solution of 4,6-dichlorofuro[3,4-
c]pyridin-3(1H)-one 9 (200 mg, 0.98 mmol) in THF (2 mL) by syringe

JOURNAL OF CHEMICAL RESEARCH 2010 113
(dd, J = 10.5 Hz and 4.4 Hz, 1H), 2.86 (ddd, J = 17.7 Hz, 4.8 Hz and
4.8 Hz, 1H), 2.63 (ddd, J = 17.7 Hz, 11.8 Hz and 5.0 Hz, 1H), 2.48–
2.35 (m, 1H), 2.25–2.10 (m, 1H). 13C NMR (50 MHz, CDCl3:CCl
7:3) δ 192.0 (s), 159.8 (s), 152.8 (s), 150.0 (s), 122.9 (s), 120.5 (d)4,
67.4 (d), 36.7 (t), 31.1 (t). Anal. Calcd for C9H7Cl2NO2: C, 46.58;
H, 3.04; N, 6.04. Found: C, 46.20; H, 2.90; N, 5.97%.
give the title compound 21 as a white crystalline solid (50 mg, 11%
yield) along with cyclised product 19 (70 mg, 16%). M.p. 135–137 °C.
1H NMR (200 MHz, CDCl3) δ 7.25 (s, 1H), 7.01 (d, J = 7.8 Hz, 2H),
6.94 (d, J = 7.8 Hz, 2H), 5.47 (s, 1H), 3.75 (s, 3H), 2.81 (dd, J = 18 Hz
and 11.4 Hz, 1H), 2.65 (dd, J = 18 Hz and 3.3 Hz, 1H), 2.27 (s, 3H),
2.14–2.0 (m, 1H), 0.40 (s, 3H), 0.25 (s, 3H). Anal. Calcd for
C H Cl2NO4Si: C, 54.80; H, 4.83; N, 3.20. Found: C, 54.27; H, 4.45;
N2,03.2012%.
Methyl 1,3-dichloro-8-hydroxyisoquinoline-7-carboxylate (18) and
methyl 1,3-dichloro-6-(dimethyl-p-tolylsilyl)-5,8-dihydroxy-5,6-dihy-
droisoquinoline-7-carboxylate (19): The experimental procedure for
the preparation of 18 and 19 were same as that described for the prep-
aration of 12 using cis-silylacrylate 17 as a Michael acceptor instead
of methyl acrylate. From 4,6-dichlorofuro[3,4-c]pyridin-3(1H)-one 9
(500 mg, 2.4 mmol) were obtained 18 (90 mg, 13%) as a white solid
and 19 (270 mg, 25% yield) as a yellowish oil.
This work was supported by DST and CSIR, Government
of India. BP is grateful to CSIR, Government of India for a
Senior Research Fellowship. The NMR facility at IITKGP was
supported by the FIST program of the DST.
1
18: M.p.169–171 °C. H NMR (400 MHz, CDCl3) δ 12.9 (s, 1H),
7.96 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 3.96
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.7 (s), 162.4 (s), 150.3 (s),
146.1 (s), 144.9 (s), 131.2 (d), 119.3 (d), 117.1 (s), 116.5 (d), 108.4
(s), 52.9 (q). Anal. Calcd for C11H Cl NO3: C, 48.56; H, 2.59; N, 5.15.
Found: C, 48.27; H, 2.45; N, 5.027%.2
Received 24 November 2009; accepted 25 January 2010
Paper 090879 doi: 10.3184/030823410X12659067482702
Published online: 3 March 2010
19: 1H NMR (200 MHz, CDCl ) δ 12.77 (s, 1H), 7.17 (s, 1H), 7.13
(d, J = 7.8 Hz, 2H), 7.03 (d, J = 73.8 Hz, 2H), 5.14 (d, J = 7.8 Hz, 1H),
3.76 (s, 3H), 2.78 (d, J = 7.9 Hz, 1H), 2.31 (s, 3H), 0.26 (s, 3H), 0.11
(s, 3H). 13C NMR (50 MHz, CDCl3) δ 172.2 (s), 161.0 (s), 157.3 (s),
154.0 (s), 151.4 (s),146.6 (s), 139.5(s), 133.6 (d), 133.2 (s), 128.4 (d),
122.2 (s), 118.4 (d), 110.2 (s), 70.6 (d), 51.9 (q), 29.4 (d), 21.3 (q),
−2.6 (q), −3.1 (q). HRMS (FAB) Calcd for C20H22Cl2NO4Si (M+H)+,
m/z 438.0694. Found 438.0690.
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1
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