A convenient method for the preparation of 4-hydroxy-2-methyl-1-oxo-1,2- dihydroisoquinoline-3-carboxylic acid derivatives

Article abstract of DOI:10.1055/s-2006-942402

An improved method for the synthesis of 4-hydroxy-2-methyl-1-oxo-1,2- dihydroisoquinoline-3-carboxylic acid derivatives is described. The synthetic route involves initial phthalic anhydride aminolysis with alkylaminoacetic acid derivatives, further esterification with diazomethane and final heterocyclization of the phthalamic ester intermediates by alkoxide-induced Dieckmann condensation. The best yields are reached for esters and N,N-disubstituted carboxamides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942402

PAPER
1971
A Convenient Method for the Preparation of 4-Hydroxy-2-methyl-1-oxo-1,2-
dihydroisoquinoline-3-carboxylic Acid Derivatives
4
-Hydroxy-2-methyl-1
a
-oxo-1, 2-di
r
hydroiso
í
quinol
a
ine-3-carboxylic
A
M
cid Derivatives ercedes Blanco, María Sol Shmidt, Celia Beatriz Schapira, Isabel Amalia Perillo*
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica (UBA), Junín 956 (1113), Buenos Aires, Argentina
Fax +54(11)49648250; E-mail: iperillo@ffyb.uba.ar
Received 13 January 2006
ed the synthesis of 4-hydroxy-2-methyl-1-oxo-1,2-dihy-
Abstract: An improved method for the synthesis of 4-hydroxy-2-
droisoquinoline-3-carboxylic acid methyl ester (1a) by
methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid deriva-
cyclization of a phthalamic acid derivative, previously
tives is described. The synthetic route involves initial phthalic an-
synthesized from monomethyl phthalate.2a In our hands,
hydride aminolysis with alkylaminoacetic acid derivatives, further
esterification with diazomethane and final heterocyclization of the obtaining the diester-free, anhydrous hemiester necessary
phthalamic ester intermediates by alkoxide-induced Dieckmann
for this strategy required several recrystallizations and re-
condensation. The best yields are reached for esters and N,N-disub-
sulted in a decrease in the overall yield.
stituted carboxamides.
The present paper describes a new approach to the synthe-
sis of 2-substituted 4-hydroxy-1-oxo-1,2-dihydroisoquin-
oline-3-carboxylic acid esters and amides (1) from
Key words: heterocycles, isoquinolinones, cyclization, lactams,
enols
phthalic anhydride with good yields. The synthetic route,
which does not require the isolation of intermediates, is
Hydroxypyridonecarboxylic acid derivatives containing
depicted in Scheme 1. It involves initial phthalic anhy-
an aromatic or heteroaromatic fused ring (A, B) represent
dride aminolysis with alkylaminoacetic acid derivatives,
a type of compound that has been of interest to many re-
further esterification with diazomethane and final hetero-
searchers. This core skeleton is central to hydroxy deriva-
cyclization of the phthalamic ester intermediates by
tives of quinolinones (A, Ar = C6H4),1 isoquinolinones
alkoxide-induced Dieckmann condensation.
(B, Ar = C6H4)2 and various naphthyridinones (A and B,
Ar = C5H3N),3 some of which possess interesting biologi-
cal properties such as immunomodulating and antiangio-
genic,1a–d,3d anti-inflammatory,2c,d,3d gastric antisecretory,3b,c
and PAI-1 inhibitory.1f
Reaction of phthalic anhydride with sarcosine ethyl ester
and further esterification lead to the phthalamic ester 2b,
which was cyclized to 1b with hot sodium ethoxide in eth-
anol. Since intermediate 2b was observed to easily under-
go transesterification, synthesis of the methyl ester 1a
could likewise be accomplished using sodium methoxide
as cyclizing agent.6–8
OH
OH
COX
O
COX
R
Ar
Ar
N
Synthesis of intermediate phthalamic esters 2c–f required
the preparation of alkylaminoacetamides by aminolysis of
the corresponding chloroacetamides. Sodium isopro-
poxide was the choice reagent for the final cyclization
step. The best overall yields were obtained for N,N-disub-
stituted 3-carboxamides 1d and 1e (75 and 78% respec-
N
R
O
A
B
Figure 1
We present here a new approach to the synthesis of 4-hy- tively). N-Monosubstituted carboxamide 1c was obtained
droxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with lower yield (64%) and considerable amounts of acid-
derivatives 1, useful, polyfunctional synthetic intermedi- ic, low Rf by-products.9
ates for the synthesis of biologically active com-
Sodium isopropoxide induced cyclization of phthalamic
esters with branched substituents on the lactam nitrogen,
pounds.2a,2d,4
N-Lactam-unsubstituted isoquinolinones (1, R = H) are such as N-tert-butyl derivative 2f, led to a complex mix-
classically obtained by alkoxide-induced rearrangement ture of products from which, besides isoquinolone 1f
of phthalimidoacetic acid derivatives.2b An alternative (8%), monomethyl phthalate (30%) was isolated as the
route involves treatment of phthalic anhydride with meth- major product.
yl isocyanoacetate.5 Since attempts at selective N-alkyla-
On the basis of literature data, the positive ferric chloride
tion of these compounds failed,2a N-substituted
test and the presence in the 1H NMR spectra of signals at-
isoquinolinones 1 (R = alkyl) had to be obtained from N-
lactam-substituted precursors. Thus, Lombardino report-
1640–1665 cm–1 range in the IR spectra and the absence
tributed to enol protons, the presence of bands in the
of signals over 165 ppm in the 13C NMR spectra, we have
depicted the enol-lactam structure for compounds 1 in
Scheme 1.
SYNTHESIS 2006, No. 12, pp 1971–1974
x
x.
x
x
.
2
0
0
6
Advanced online publication: 06.06.2006
DOI: 10.1055/s-2006-942402; Art ID: M00206SS
© Georg Thieme Verlag Stuttgart · New York

1972
M. M. Blanco et al.
PAPER
OH
O
O
CO2CH3
COX
R
1) RNH-CH2-COX
2) CH2N2
NaRO
ROH
O
N
CO-N-CH2-COX
R
O
2
1
Scheme 1
Cyclizations of compounds 2 were performed by treating the crude
products (1.1 g) dissolved in the appropriate boiling alcohol (3 mL)
with sodium alkoxide (2 M, 3 mL) and refluxed for 30 min (sodium
isopropoxide–isopropanol was used to perform ring closure for
compounds 2c–f and the couple alkoxide–alcohol corresponding to
the ester alkyl group for compounds 2a,b). The red-yellow syrup
was poured into ice–HCl (1 M, 5 mL) and extracted with CHCl3
(4 × 5 mL). After washing with H2O the organic layer was dried,
concentrated in vacuo and purified by centrifugal PLC affording
compounds 1a–f. In the case of N-tert-butyl derivative 2f cycliza-
tion, a complex mixture of products was obtained, from which iso-
quinolinone 1f (8%) and monomethyl phthalate (30%, mp 84 °C)
were isolated.
Table 1
Compds 1,2
R
X
a
b
c
d
e
f
Me
Me
Me
Me
Me
t-Bu
OMe
OEt
NHEt
N(Me)Ph
NEt2
N(Me)Ph
4-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-
3-carboxylic Methyl Ester (1a)
Yield: 83%; mp 93–95 °C (2-propanol) (Lit.2a 93–94 °C).
In summary, we have developed an improved method for
the synthesis of 4-hydroxy-1-oxo-1,2-dihydroisoquino-
line-3-carboxylic acid derivatives N-methyl substituted
on the lactam nitrogen, with good yields. In particular, we
must emphasize that the present synthetic strategy allows
access to enolcarboxamides 1 (X = NRR¢) from phthalic
anhydride in a three-step synthesis, thus avoiding multi-
step routes previously described in the literature.2a,2d
1H NMR (CDCl3): d = 11.20 (br s, 1 H, OH), 8.48 (d, J = 7.8 Hz,
1 H, H-8), 8.18 (d, J = 7.8 Hz, 1 H, H-5), 7.76 (t, J = 7.8 Hz, 1 H,
H-6), 7.70 (t, J = 7.8 Hz, 1 H, H-7), 3.98 (s, 3 H, OCH3), 3.40 (s,
3 H, NCH3).
13C NMR (DMSO-d6): d = 165.9, 160.9, 143.5, 133.9, 131.5, 129.6,
128.3, 127.1, 123.7, 116.5, 54.3, 36.1.
MS (EI, 70 eV): m/z (%) = 233 (26) [M]+, 190 (100).
4-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-
3-carboxylic Ethyl Ester (1b)
Yield: 78%; mp 119–121 °C (2-propanol).
IR (KBr): 3390–3500, 1662, 1645, 1580, 1300 cm–1.
1H NMR (CDCl3): d = 11.22 (br s, 1 H, OH), 8.46 (d, J = 7.9 Hz,
1 H, H-8), 8.15 (d, J = 7.9 Hz, 1 H, H-5), 7.76 (t, J = 7.9 Hz, 1 H,
H-6), 7.72 (t, J = 7.9 Hz, 1 H, H-7), 4.49 (q, J = 7.2 Hz, 2 H, OCH2),
3.36 (s, 3 H, NCH3), 1.45 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (CDCl3): d = 166.8, 160.5, 149.8, 132.3, 131.1, 130.0,
128.6, 128.1, 123.5, 111.7, 62.6, 36.4, 14.2.
Melting points were taken on a Büchi capillary apparatus and are
uncorrected. The 1H and 13C NMR spectra were recorded on a Bruk-
er MSL at 300 MHz. Chemical shifts are quoted in parts per million
(d) downfield from an internal TMS reference. The presence of ex-
changeable protons was confirmed by use of deuterium oxide. MS
(EI) were performed on a MS Shimadzu QP-1000 instrument. The
IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR
spectrometer. Analytical TLC was carried out on aluminum sheets
Silica Gel 60 F254. Preparative thin layer separations (PLC) were
carried out by radial chromatography using Chromatotron model
7924T. The rotors were coated with Silica Gel 60 PF254 and the layer
thickness was 2 mm. CHCl3 and increasing percentages of MeOH
were used as eluent. Reagents, solvents and starting materials were
purchased from standard sources and purified according to litera-
ture procedures.
MS (EI, 70 eV): m/z (%) = 247 (20) [M]+, 190 (100).
Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C,
63.22; H, 5.34; N, 5.59.
4-Hydroxy-2-methyl-1-oxo-N-phenyl-1,2-dihydroisoquinoline-
3-carboxamide (1c)
2-Substituted 4-Hydroxy-1-oxo-1,2-dihydroisoquinoline-
3-carboxylic Acid Derivatives; General Procedure
Yield: 64%; mp 253–255 °C (2-propanol)10.
IR (KBr): 3550–3200, 1658, 1642, 1579 cm–1.
To a mixture of phthalic anhydride (0.74 g, 5 mmol), the appropriate
alkylaminoacetic acid derivative hydrochloride (6 mmol) and dry
THF (10 mL) at 0 °C, was added dropwise, with stirring Et3N (0.81
g, 8 mmol) in THF (10 mL). After stirring for 1 h at r.t., the reaction
mixture was cooled to 0 °C, filtered and the filtrate was concentrat-
ed in vacuo. The pasty solid was dissolved in anhydrous MeOH (5
mL) and a solution of CH2N2 in Et2O (1% P/V, ca. 30 mL) was add-
ed in small portions until the solution acquired a pale-yellow color.
After 24 h at r.t., the reaction mixture was concentrated in vacuo af-
fording the phthalamic esters 2 which were used in the next step
without purification.
1H NMR (DMSO-d6): d = 10.76 and 9.01 (br s, 2 H, OH and NH),
8.31 (d, J = 7.2 Hz, 1 H, H-8), 8.00 (d, J = 7.2 Hz, 1 H, H-5), 7.83
(t, J = 7.2 Hz, 1 H, H-6), 7.76 (d, J = 7.7 Hz, 2 H, NHAr, Hortho),
7.63 (t, J = 7.2 Hz, 1 H, H-7), 7.39 (t, J = 7.7 Hz, 2 H, NHAr, Hmeta),
7.15 (t, J = 7.7 Hz, 1 H, NHAr, Hpara), 3.48 (s, 3 H, NCH3).
13C NMR (DMSO-d6): d = 160.5, 159.1, 138.6, 133.1, 132.1, 131.9,
128.8, 127.8, 127.4, 125.6, 125.0, 124.1, 122.0, 119.6, 32.3.
MS (EI, 70 eV): m/z (%) = 294 (8) [M]+, 175 (100) [M –
OCNC6H5]+.
Synthesis 2006, No. 12, 1971–1974 © Thieme Stuttgart · New York

PAPER
4-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid Derivatives
1973
Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.46; H, 4.84; N, 9.45.
Runström, A.; Sandin, H.; Thuvesson, I.; Björk, A. J. Med.
Chem. 2004, 47, 2075; and references cited therein.
(d) Brunmark, C.; Runström, A.; Ohlsson, L.; Sparre, B.;
Brodin, T.; Aström, M.; Hedlund, G. J. Neuroimmunol.
2002, 130, 163. (e) Tsuji, K.; Spears, G. W.; Nakamura, K.;
Tojo, T.; Seki, N.; Sugiyama, A.; Matsuo, M. Bioorg. Med.
Chem. Lett. 2002, 12, 85. (f) Folkes, A.; Brown, S. D.;
Canne, L. E.; Chan, J.; Engelhardt, E.; Epshteyn, S.; Faint,
R.; Golec, J.; Hanel, A.; Kearney, P.; Leahy, J. W.; Mac, M.;
Matthews, D.; Prisbilla, M. P.; Sanderson, J.; Simon, R. J.;
Tesfai, Z.; Vicker, N.; Wang, S.; Webb, R. R.; Charlton, P.
Bioorg. Med. Chem. Lett. 2002, 12, 1063. (g) Ukrainets, I.
V.; Taran, S. G.; Gorokhova, O. V.; Taran, E. A.; Jaradat, N.
A.; Petukhova, I. Y. Chem. Heterocycl. Compd. (Engl.
Transl.) 2000, 36, 166. (h) Ukrainets, I. V.; Taran, S. G.;
Likhanova, N. V.; Rybakov, V. B.; Gorokhova, O. V.;
Jaradat, N. A. Chem. Heterocycl. Compd. (Engl. Transl.)
2000, 36, 49. (i) Kugalowski, J. J.; Baker, R.; Curtis, N. R.;
Leeson, P. D.; Mawer, I. M.; Moseley, A. M.; Ridgill, M. P.;
Rowley, M.; Stansfield, I.; Foster, A. C.; Grimwood, S.; Hill,
R. G.; Kemp, J. A.; Marshall, J. R.; Saywell, K. L.;
Tricklebank, M. D. J. Med. Chem. 1994, 37, 1402.
(2) Among others, see: (a) Lombardino, J. G. J. Heterocycl.
Chem. 1970, 7, 1057. (b) Schapira, C. B.; Abasolo, M. I.;
Perillo, I. A. J. Heterocycl. Chem. 1985, 22, 577; and
references cited therein. (c) Kadin, S. B.; Wiseman, E. H.
Nature 1969, 222, 275. (d) Lazer, E.; Miao, C. K.; Cywin,
C. L.; Sorcek, R.; Wong, H.-C.; Meng, Z.; Potocki, I.;
Hoermann, M.; Snow, R. J.; Tschantz, M. A.; Kelly, T. A.;
McNeil, D. W.; Coutts, S. J.; Churchill, L.; Graham, V.;
David, E.; Grob, P. M.; Engel, W.; Meier, H.; Trummlitz, G.
J. Med. Chem. 1997, 40, 980.
4-Hydroxy-N,2-dimethyl-1-oxo-N-phenyl-1,2-dihydroisoquino-
line-3-carboxamide (1d)
Yield: 75%; mp 171–174 °C (2-propanol).
IR (KBr): 3400–3160, 1652, 1645, 1584, 1375 cm–1.
1H NMR (CDCl3): d = 8.34 (br s, 1 H, OH), 7.90 (d, J = 7.8 Hz, 1 H,
H-8), 7.70 (d, J = 7.8 Hz, 1 H, H-5), 7.55 (t, J = 7.8 Hz, 1 H, H-6),
7.36 (t, J = 7.8 Hz, 1 H, H-7), 7.30–7.22 (m, 5 H, ArH), 3.52 (s, 3 H,
NCH3), 3.28 (s, 3 H, NCH3).
13C NMR (CDCl3): d = 165.3, 159.4, 141.6, 133.5, 131.6, 129.4,
129.3, 128.7, 128.2, 128.0, 127.6, 125.3, 122.3, 121.2, 37.9, 33.2.
MS (EI, 70 eV): m/z (%) = 308 (39) [M]+, 107 (100)
[NH(CH3)C6H5]+.
Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
70.22; H, 5.27; N, 9.01.
N,N-Diethyl-4-hydroxy-2-methyl-1-oxo-1,2-dihydroisoquino-
line-3-carboxamide (1e)
Yield: 78%; colorless oil.
IR (film): 3410–3200, 1650, 1638, 1580, 1372 cm–1.
1H NMR (CDCl3): d = 8.45 (br s, 1 H, OH), 8.36 (dd, J1 = 7.6,
J2 = 1.5 Hz, 1 H, H-8), 8.22 (dd, J1 = 7.6, J2 = 1.5 Hz, 1 H, H-5),
7.91 (dt, J1 = 7.6, J2 = 1.5 Hz, 1 H, H-6), 7.83 (dt, J1 = 7.6, J2 = 1.5
Hz, 1 H, H-7), 3.60–3.45 (br s, 4 H, NCH2),11 3.50 (s, 3 H, NCH3),
1.20 (m, 6 H, CH2CH3).11
13C NMR (CDCl3): d = 166.4, 160.1, 140.8, 132.4, 131.1, 130.0,
128.5, 128.0, 123.5, 111.9, 42.5, 38.6, 31.9, 13.8, 12.4.
(3) Among others, see: (a) Blanco, M. M.; Schapira, C. B.;
Levin, G.; Perillo, I. A. J. Heterocycl. Chem. 2005, 42, 493;
and references cited therein. (b) Scotese, A. C.; Santilli, A.
A. S. African ZA 8000631, 1981; Chem. Abstr. 1982, 96,
6706. (c) Scotese, A. C.; Morris, R. L.; Santilli, A. A. US
Patent 4301281, 1981; Chem. Abstr. 1982, 97, 23815.
(d) Armitage, B. J.; Leslie, B. W. PCT Int. Appl. WO
9611199, 1996; Chem.Abstr. 1996, 125, 114712.
MS (EI, 70 eV): m/z (%) = 274 (15) [M]+, 72 (100) [N(C2H5)2]+.
Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C,
65.58; H, 6.66; N, 10.14.
2-tert-Butyl-4-hydroxy-N-methyl-1-oxo-N-phenyl-1,2-dihydro-
isoquinoline-3-carboxamide (1f)
Yield: 8%; colorless oil.
IR (film): 3400–3100, 1654, 1645, 1589, 1370 cm–1.
1H NMR (CDCl3): d = 8.42 (br s, 1 H, OH), 8.31 (d, J = 7.7 Hz, 1 H,
H-8), 7.93 (d, J = 7.7 Hz, 1 H, H-5), 7.86 (t, J = 7.7 Hz, 1 H, H-6),
7.76–7.45 (m, 6 H, ArH), 3.27 (s, 3 H, NCH3), 1.34 (s, 9 H,
C(CH3)3).
(e) Nuebling, C.; Von Deyn, W.; Theobald, H.; Westphalen,
K.-O.; Kardorff, U.; Helmut, W.; Kappe, T.; Gerber, M. Ger.
Offen. DE 4227747, 1993; Chem. Abstr. 1994, 120,
323554z.
(4) Among others, see: (a) Toyama, M.; Otomasu, H. Chem.
Pharm. Bull. 1985, 33, 5543. (b) Alonso-Silva, I. J.; Pardo,
M.; Soto, J. L. Heterocycles 1988, 27, 357. (c)Beattie,J. F.;
Hales, N. J. J. Chem. Soc., Perkin Trans. 1 1992, 751.
(d) Khalaj, A.; Adibpour, N. Heterocycles 1999, 51, 131.
(5) (a) Suzuki, M.; Nunami, K.; Matsumoto, K.; Yoneda, N.;
Miyoshi, M. Synthesis 1978, 461. (b) Nunami, K.; Suzuki,
M.; Matsumoto, K.; Miyoshi, M.; Yoneda, N. Chem. Pharm.
Bull. 1979, 27, 1373. (c) Miyoshi, S.; Yoneda, N.;
Matsumoto, K.; Suzuki, M.; Nunami, K. Jpn. Kokai Tokkio
Koho 7970285, 1979; Chem. Abstr. 1979, 91, 175221.
(6) Ease of trans-esterification is related to the presence of an
electron-withdrawing group at the a-position to the ester
(ref. 7) and it was also observed in Dieckmann cyclizations
which lead to hydroxy derivatives of related heterocycles
(ref. 8).
(7) Janczewski, D.; Synoradzki, L.; Wlostowski, M. Synlett
2003, 420.
(8) Blanco, M. M.; Perillo, I. A.; Schapira, C. B. J. Heterocycl.
Chem. 1999, 36, 979; and references cited therein.
(9) This fact is related to the acid character of aniline hydrogen
in phthalamic ester 2c which would allow its deprotonation
in basic medium, thus resulting in a less probable formation
MS (EI, 70 eV): m/z (%) = 350 (4) [M]+, 134 (100)
[CON(CH3)C6H5]+.
Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C,
72.09; H, 6.38; N, 8.16.
Acknowledgment
This work was financially supported by the Universidad de Buenos
Aires.
References
(1) Among others: (a) Khan, S. R.; Mhaka, A.; Pili, R.; Isaacs,
J. T. Bioorg. Med. Chem. Lett. 2001, 11, 451. (b) Shi, J.;
Xiao, Z.; Ihnat, M. A.; Kamat, C.; Pandit, B.; Hu, Z.; Li, P.
K. Bioorg. Med. Chem. Lett. 2003, 13, 1187. (c) Jönsson,
S.; Andersson, G.; Fex, T.; Fristedt, T.; Hedlund, G.;
Jansson, K.; Abramo, L.; Fritzson, I.; Pekarski, O.;
Synthesis 2006, No. 12, 1971–1974 © Thieme Stuttgart · New York

1974
M. M. Blanco et al.
PAPER
of the carbanion necessary for the heterocyclization. A
similar behavior was observed in the alkoxide promoted
cyclization of compounds structurally related to 2c (ref. 3a).
(11) The nonresolved multiplicity of the methylene and methyl
signals is related to stereochemical features of this type of
amides: partial double bond character of CO–N amide bond
and/or the diastereotopicity of the methylene hydrogens
associated with the presence of a chiral axis (ref. 4a).
(10) Lombardino (ref. 2a) describes the reaction product as a
solid, formula: C17H14N2O3·0.5H2O, mp 195–197 °C.
Synthesis 2006, No. 12, 1971–1974 © Thieme Stuttgart · New York