Concise syntheses of the novel 1H-pyrrolo[3,2-g]quinazoline ring system and its [2,3-f] angular isomer

Full text of DOI:10.1021/jo951790b

J . Org. Chem. 1996, 61, 1155-1158
1155
cidin,8 which is highly stable toward acid hydrolysis, and
a series of novel antifolate inhibitors of dihydrofolate
reductases,9 respectively.
Con cise Syn th eses of th e Novel
1H-P yr r olo[3,2-g]qu in a zolin e Rin g System
a n d its [2,3-f] An gu la r Isom er
H. D. Hollis Showalter,*,† Li Sun,† Anthony D. Sercel,†
R. Thomas Winters,† William A. Denny,‡ and
Brian D. Palmer‡
Chemistry Department, Parke-Davis Pharmaceutical
Research, Division of Warner-Lambert Company, 2800
Plymouth Road, Ann Arbor, Michigan 48106-1047 and
Cancer Research Laboratory, University of Auckland School
of Medicine, Private Bag 92019, Auckland, New Zealand
Resu lts a n d Discu ssion
Received October 2, 1995
To construct our targeted 1H-pyrrolo[3,2-g]quinazoline
ring system, exemplified by 3, we initially adopted a
strategy whereby the indole ring would be annulated via
Batcho-Leimgruber indole synthesis10 onto a 7-nitro-
quinazolinone precursor 8 (Scheme 1, route a). Accord-
ingly, nitration of 6-methylquinazolin-4-one11 (9) was
evaluated under a number of conditions. However, this
provided predominately the 5-nitro isomer3c,4d,e instead
of the desired 7-isomer 8. Thus, we pursued the con-
struction of 3 by a reverse sequence in which pyrimidine
ring annulation was carried out on a suitably function-
alized indole precursor 10 (Scheme 1, route b).
In tr od u ction
Several years ago, Leonard and co-workers reported
on the synthesis of a series of linear benzo-substituted
purines, agents that act as purine mimics in many
enzymatic reactions.1 These are chemically designated
as imidazo[4,5-g]quinazolines and are exemplified by lin-
benzohypoxanthine (1). There soon followed the synthe-
sis of a number of angular analogues2 including the
imidazo[4,5-f] series of compounds exemplified by prox-
benzohypoxanthine (2). More recently, others have
extended this work to the synthesis of isomeric forms of
these tricycles including linear3 and angular4 pyrazolo-
quinazoline systems. However, reports describing the
synthesis of corresponding benzo-substituted deazapu-
rines (i.e., pyrroloquinazolines) are sparse. Apart from
the synthesis of a single angular isomer (pyrrolo[3,2-f]-
quinazoline)5 of this heterocyclic system, these ring
systems have never been made. We report in this paper
approaches toward the first synthesis of a linear pyr-
roloquinazoline and one of its angular isomers, exempli-
fied by compounds 3 and 4, respectively. Heterocycle 3
can be viewed as a linear extension of the deazapurine
56 (i.e., pyrrolo[2,3-d]pyrimidine ring system), which is
an important precursor of the 4-amino analogue 6.7
Heterocycle 6 and its 2-amino derivative 7 are structural
elements of the important antitumor nucleoside tuber-
Sch em e 1
The synthesis of linear target 3 is shown in Scheme 2.
Fischer esterification of commercially available 3-methyl-
4-nitrobenzoic acid (12) gave ethyl ester 1312 in 92% yield,
which was then nitrated regioselectively with cold fuming
nitric acid to afford an 86:14 mixture of desired product
1413 and its isomer 15 in 98% yield. Ester 14 was
purified to >97% isomeric purity in an overall yield of
70% by crystallization from 2-propanol. At this juncture,
14 could be parlayed into target compound 3 by one of
two routes. In the first, Batcho-Leimgruber indole
synthesis was performed by condensation of 14 with DMF
dimethyl acetal in refluxing p-dioxane to cleanly give the
enamino ester 16, which was not isolated but was directly
reductively cyclized via catalytic hydrogenation to the
indolic anthranilate 17 in 96% yield. Indole 17 was
contaminated with 4-10% of the corresponding 1-hy-
† Parke-Davis Pharmaceutical Research.
‡ University of Auckland School of Medicine.
(1) (a) Leonard, N. J .; Morrice, A. G.; Sprecker, M. A. J . Org. Chem.
1975, 40, 356-363. (b) Moder, K. P.; Leonard, N. J . J . Am. Chem. Soc.
1982, 104, 2613-2624. (c) Leonard, N. J .; Kazmierczak, F.; Rykowski,
A. Z. J . Org. Chem. 1987, 52, 2933-2935. (d) Leonard, N. J .; Petric,
A.; Rykowski, A. J . Org. Chem. 1988, 53, 3873-3875.
(2) Imidazo[4,5-f]quinazolines: (a) Morrice, A. G.; Sprecker, M. A.;
Leonard, N. J . J . Org. Chem. 1975, 40, 363-366. (b) Schneller, S. W.;
Ibay, A. C. J . Org. Chem. 1986, 51, 4067-4070. Imidazo[4,5-h]-
quinazolines: (c) ref 2a.
(3) Pyrazolo[3,4-g]quinazolines: (a) Lichtenthaler, F. W.; Moser, A.
Tetrahedron Lett. 1981, 22, 4397-4400. Pyrazolo[4,3-g]quinazolines:
(b) Foster, R. H.; Leonard, N. J . J . Org. Chem. 1979, 44, 4609-4611.
(c) Cuny, E.; Lichtenthaler, F. W.; Moser, A. Tetrahedron Lett. 1980,
21, 3029-3032. (d) Cuny, E.; Lichtenthaler, F. W.; J ahn, U. Chem.
Ber. 1981, 114, 1624-1635.
(4) Pyrazolo[3,4-h]quinazolines: (a) ref 3a; Pyrazolo[4,3-f]-
quinazolines: (b) ref 3d; Pyrazolo[3,4-f]quinazolines: (c) ref 3c. (d)
Foster, R. H.; Leonard, N. J . J . Org. Chem. 1980, 45, 3072-3077. (e)
Lichtenthaler, F. W.; Cuny, E. Heterocycles 1981, 15, 1053-1059.
(5) (a) J ones, M. L.; Kuyper, L. F.; Styles, V. L.; Caddell, J . M. J .
Heterocycl. Chem. 1994, 31, 1681-1683. (b) Kuyper, L. F.; J ones,
Michael L.; Baccanari, D. P. European Patent Application 542497;
Chem. Abstr. 1994, 120, 8606u.
(8) Anderson, J . D.; Bontems, R. J .; Geary, S.; Cottam, H. B.; Larson,
S. B.; Matsumoto, S. S.; Smee, D. F.; Robins, R. K. Nucleosides
Nucleotides 1989, 8, 1201-1216.
(9) Gangjee, A.; Mavandadi, F.; Queener, S. F.; McGuire, J . J . J .
Med. Chem. 1995, 38, 2158-2165.
(10) Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195-221.
(11) Stevenson, T. M.; Kazmierczak, F.; Leonard, N. J . J . Org. Chem.
1986, 51, 616-21.
(6) Seela, F.; Richter, R. Chem. Ber. 1978, 111, 2925-2930.
(7) Seela, F.; Menkhoff, S.; Behrendt, S. J . Chem. Soc., Perkin Trans.
2 1986, 525-530.
(12) Beilstein, F.; Kreusler, U. J ustus Liebigs Ann. Chem. 1867, 144,
163-184.
(13) Blatt, A. H. J . Org. Chem. 1960, 25, 2030-2034.
0022-3263/96/1961-1155$12.00/0 © 1996 American Chemical Society

1156 J . Org. Chem., Vol. 61, No. 3, 1996
Notes
Sch em e 2a
refluxing 2-methoxyethanol to provide target compound
3 without any N-hydroxy impurity. More classical
methods of ring closure including the Niementowski
reaction (hot formamide)16 and s-triazine in refluxing
alcohol17 failed.
In a second route to 3, shown in Scheme 2, aminolysis
of dinitro ester 14 to amide 1918 followed by condensation
with tert-butoxybis(dimethylamino)methane (Bredereck’s
reagent) in DMF at room temperature afforded the
enamino amidine 20 as a brick red solid in 76% yield over
two steps.19 Similar reaction with DMF dimethyl acetal
proceeded much less cleanly. Since 20 contains the
necessary framework for further elaboration to target 3
via tandem ring closure, we subjected it to various
conditions of reductive cyclization, including numerous
conditions of catalytic hydrogenation over 10% Pd/C, and
selected dissolving metal reductions.20 Amongst these,
the best condition developed involved high pressure
Raney nickel hydrogenation in 1:1 THF:MeOH21 at high
dilution to afford compound 3 in 57% yield on a small
scale. However, larger scale reactions were highly irre-
producible, with 10-15% yields the norm. Thus, we
found it more convenient to selectively hydrolyze the
amidine side chain of 20 with mildly acidic methanol to
give the enamino amide 21 in 80% yield. Reductive ring
closure similar to that described above for 16 gave the
indole amide 22 in 72% yield.22 Compound 22 as well
as 17 are quite air sensitive and darken while in solution.
Ring closure of 22 to target 3 proceeded uneventfully in
hot triethyl orthoformate. Solutions of 3 in common
organic solvents are also unstable, but it can be stored
as a solid without significant decomposition.
The synthesis of angular target compound 4, shown
in Scheme 3, proceeded in a much more straightforward
fashion. Thus, Fischer esterification of 3-methyl-6-ni-
trobenzoic acid 23 provided ester 24 in 91% yield.
Nitration of 24 with fuming nitric acid in triflic acid23
proceeded to give a 1:1 mixture of compound 2513 and
its regioisomer 14 in 61% yield. Following separation by
careful column chromatography, bis-nitro ester 25 was
condensed with DMF dimethyl acetal in DMF at 100 °C
(15) Albert, A. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic: New York, 1982; Vol 32, pp 1-81.
(16) Irwin, W. J .; Wibberley, D. G. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic: New York,
1969; Vol 10, pp 149-198.
a
(17) Kreutzberger, A.; Uzbek, M. U. Arch. Pharm. (Weinheim) 1972,
305, 171-175.
Key: (a) EtOH, H2SO4, reflux, 24 h, 92%; (b) fuming HNO3,
H2SO4, -20 °C, 5.75 d, 70%; (c) DMFDMA, p-dioxane, reflux, 1.5
h; (d) 5% Pd/C, H2 (60 psi), MeOH, 1 h, 96% two steps; (e)
formamidine acetate, 2-methoxyethanol, reflux, 2 h, 64%; (f) anhyd
NH3/MeOH, 80 °C, 12 h, 90%; (g) BBDM, DMF, 25 °C, 1 h, 84%;
(h) MeOH, glacial HOAc, reflux, 2 d, 80%; (i) 10% Pd/C, H2, THF,
12 h, 72%; (j) (EtO)3CH, 100 °C, 1 h, 50%; (k) RaNi, H2 (1500 psi),
1:1 THF:MeOH, 25 °C, 57%.
(18) Piskov, V. B.; Osanova, L. K.; Koblova, I. A. Zh. Org. Khim.
1970, 6, 559-564; Chem. Abstr. 1970, 72, 132251d.
(19) It is imperative to use pure (tert-butyloxy)bis(dimethylamino)-
methane in this reaction. In one run utilizing old reagent, the reaction
did not proceed cleanly. Attempted purification of crude 20 by column
chromatography resulted in significant decomposition, in part to amide
21.
(20) (a) Aqueous TiCl3: Lloyd, D. H.; Nichols, D. E. Tetrahedron
Lett. 1983, 24, 4561-4562. (b) Fe/HOAc/EtOH: Ponticello, G. S.;
Baldwin, J . J . J . Org. Chem. 1979, 44, 4003-4005. (c) Zn/HOAc:
Glushkov, R. G.; Volskova, V. A.; Magidson, O. Y. Khim.-Farm. Zh.
1967, 1, 25-32; Chem. Abstr. 1968, 68, 105143f.
droxyindole 18 that displayed the same Rf by TLC.14
Annulation of the pyrimidinone ring onto 17 proceeded
smoothly in 64% yield with formamidine acetate15 in
(21) Hengartner, U.; Batcho, A. D.; Blount, J . F.; Leimgruber, W.;
Larscheid, M. E.; Scott, J . W. J . Org. Chem. 1979, 44, 3748-3752.
(22) In a separate run in which the reaction was worked up before
there was theoretical uptake of H2, we isolated a component, mp 171
°C dec, ca. 87% pure by 1H NMR, that displayed the same Rf by TLC
as desired product 22. Its 1H NMR and CIMS suggest that it is the
intermediate 1-hydroxy analogue of 22, corresponding to 18 observed
in the reduction 16 to 17;14 1H NMR (Me2SO-d6) δ 10.92 (s, exchanges
with D2O, 1H), 7.74 (s, 1H), 7.65 (br s, exchanges with D2O, 1H), 7.15
(d, J ) 3.4 Hz, 1H), 6.94 (br s, exchanges with D2O, 1H), 6.55 (s, 1H),
6.22 (s, exchanges with D2O, 2H), 6.11 (d, J ) 3.4 Hz, 1H); CIMS m/ z
(relative intensity) 192 (14), 191(M+, 40), 175 (100), 174 (43).
(23) Coon, C. L.; Hill, M. E. U.S. Patent 3714272; Chem. Abstr. 1973,
78, 97303x.
(14) Although 18 is not observed in the EIMS of the mixture, it is
evident by high-field NMR. Thus, in the Me2SO-d6 1H NMR spectrum
of the mixture of 17 and 18, H-2 and H-3 of the indole ring of 17
resonate at δ 7.09 and 6.29, respectively, and display couplings to the
indolic NH proton as well as to each other. Impurity 18 is evidenced
by the presence of the additional resonances at δ 7.30 and 6.23, which
are coupled only to each other, and another exchangeable resonance
at δ 5.87. In the CDCl3 13C NMR spectrum, there are additional
resonances at δ 132.96, 122.93, 100.02, 59.64 and 16.26. The 132.96
and 100.02 signals are the most prominent, and correspond to CH
carbons from the DEPT spectrum. Therefore, they most likely cor-
respond to C-2 and C-3, respectively, of 18.

Notes
J . Org. Chem., Vol. 61, No. 3, 1996 1157
Sch em e 3a
gave 133 g of an oil that solidified as an 86:14 mixture of isomers
(monitored by 1H NMR or TLC utilizing 4:1 hexanes:EtOAc).
The crude solid was triturated in 150 mL of i-PrOH and then
filtered to leave a pale white solid. The solid was dissolved in
400 mL of hot i-PrOH, and the solution was allowed to slowly
cool to 25 °C. After storage the solid was collected, washed with
i-PrOH, and dried to leave 95 g (70%) of 14, 98% by 1H NMR,
as a white solid: mp 60.5-62.5 °C (lit.13 mp 47-48 °C): 1H NMR
(Me2SO-d6) δ 8.61 (s, 1H), 8.00 (s, 1H), 4.32 (q, J ) 7.1 Hz, 2H),
2.63 (s, 3H), 1.24 (t, J ) 7.1 Hz, 3H); 13C NMR (Me2SO-d6) δ
164.1, 149.8, 145.4, 140.2, 134.4, 130.7, 121.3, 63.2, 19.8, 14.0;
CIMS m/ z (relative intensity) 255 (MH+, 36). Anal. Calcd for
C
10H10N2O6: C, 47.25; H, 3.97; N, 11.02. Found: C, 47.53; H,
4.05; N, 11.00.
The filtrate was concentrated to a ca. 1:1 mixture of isomers.
Dissolution of the solid in dilute 2:1 hexanes:i-PrOH followed
by storage at 25 °C for several weeks resulted in the crystal-
lization of >90% pure material. An additional crystallization
from i-PrOH gave pure 15: mp 75.5-76 °C: 1H NMR (CDCl3) δ
8.04 (d, J ) 8.7 Hz, 1H), 7.99 (d, J ) 8.7 Hz, 1H), 4.41 (q, J )
7.0 Hz, 2H), 2.45 (s, 3H), 1.38 (t, J ) 7.2 Hz, 3H); CIMS m/ z
(relative intensity) 255 (MH+, 36), 209 (100). Anal. Calcd for
a
Key: (a) EtOH, H2SO4, reflux, 2 d, 91%; (b) fuming HNO3,
CF3SO3H, CH2Cl2, 25 °C, 20 h, 31%; (c) DMFDMA, DMF, 100 °C,
4 h, 70%; (d) 10% Pd/C, H2 (50 psi), MeOH, 4 h, 48% (e) formamide,
150-180 °C, 3 h, 44%.
C
10H10N2O6: C, 47.25; H, 3.97; N, 11.02. Found: C, 47.31; H,
3.97; N, 11.03.
6-Am in o-1H-in d ole-5-ca r boxylic Acid , Eth yl Ester (17).
A solution of 15.0 g (59 mmol) of ester 14 and 9.4 mL (71 mmol)
of DMF dimethyl acetal in 250 mL of p-dioxane was heated at
reflux for 1.5 h. The resulting deep red solution, containing (E)-
5-[2-(dimethylamino)ethenyl]-2,4-dinitrobenzoic acid, ethyl ester
(16) as the sole product, was cooled to 25 °C, diluted with 100
mL of MeOH and then hydrogenated at 60 psi over 8.0 g of 5%
Pd/C. After 1 h, when H2 uptake had ceased, the mixture was
filtered and concentrated to give a solid that was purified by
column chromatography. Elution with EtOAc/petroleum ether
(1:1) afforded 11.6 g (96%) of 17, contaminated with ca. 4% of
the corresponding 1-hydroxyindole 18.14 Crystallization from
aq MeOH provided pure 17: mp 139 °C; 1H NMR (Me2SO-d6) δ
10.68 (br s, exchanges with D2O, 1H), 8.02 (s, 1H), 7.09 (dd, J )
3.1, 2.4 Hz, 1H), 6.64 (s, 1H), 6.29 (m, 1H), 6.18 (br s, exchanges
with D2O, 2H), 4.24 (q, J ) 7.0 Hz, 2H), 1.32 (t, J ) 7.0 Hz, 3H);
13C NMR (CDCl3) δ 168.8, 146.4, 140.5, 124.8, 123.9, 120.6,
107.9, 103.5, 96.0, 60.1, 14.5; EIMS m/ z (relative intensity) 204
(M+, 92), 158 (100), 130 (59), 104 (19). Anal. Calcd for
to afford compound 26 in 70% yield. Reductive cycliza-
tion of 26 via catalytic hydrogenation to indole 27
followed by condensation with formamide at 100 °C gave
target pyrrolo[2,3-f]quinazolinone 4 in 21% yield over two
steps. Yields for the synthesis of angular target 4 were
not optimized.
In summary, we have developed synthetic pathways
to two novel pyrroloquinazoline heterocycles, benzo-
substituted variants of the biologically important pyrrolo-
[2,3-d]pyrimidine ring system. We expect these hetero-
cycles to find broad application as novel templates in
organic synthesis and drug design.
Exp er im en ta l Section
C
11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.39; H,
6.04; N, 13.44.
Melting points are uncorrected. Column chromatography was
carried out in the flash mode utilizing E. Merck 230-400-mesh
silica gel. Analytical TLC was carried out on E. Merck silica
gel 60 F254 plates with detection by UV light. Palladium on
activated carbon utilized in catalytic hydrogenations was pur-
chased from Aldrich Chemical Co. All reaction solvents were
reagent grade or distilled-in-glass and were stored over activated
3A (for lower alcohols) or 4A molecular sieves. Following normal
workup procedures, organic extracts were dried over anhyd Na2-
SO4 or MgSO4 prior to concentration.
3-Meth yl-4-n itr oben zoic Acid , Eth yl Ester (13). A solu-
tion of 102.1 g (564 mmol) of 3-methyl-4-nitrobenzoic acid (12)
dissolved in 1 L of absolute EtOH was carefully treated with 10
mL of concd H2SO4. The solution was heated at reflux for 24 h
then concentrated to 300 mL by allowing the EtOH to distill
off. Upon cooling solids precipitated. The suspension was
further cooled to about -10 °C, and then the solids were
collected, washed with a small amount of cold EtOH, and
recrystallized from 450 mL of boiling hexanes to afford 108 g
(92%) of 13 as a pale yellow solid: mp 52.5-53.5 °C (lit.12 mp
55 °C); 1H NMR (CDCl3) δ 11.53 (s, 1H), 7.98-7.93 (m, 3H), 4.38
(q, J ) 7.0 Hz, 2H), 2.58 (s, 3H), 1.38 (t, J ) 7.0 Hz, 3H). Anal.
Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C,
57.23; H, 5.25; N, 6.65.
4,6-Din itr o-m -tolu ic Acid , Eth yl Ester (14). A solution of
112 g (535 mmol) of ester 13 in 460 mL of concd H2SO4 was
cooled to -10 °C and then treated dropwise over a 45 min period
with 106 mL of fuming HNO3 so as to maintain the internal
temperature at -10 °C. The solution was stored at -20 °C for
5.75 d. The resulting golden yellow syrup was carefully poured
into about 3.2 L of crushed ice precipitating out a waxlike solid.
The suspension was extracted into EtOAc (3 × 600 mL), and
the combined extracts were washed with 5% aq NaOH until the
aqueous phase remained neutral and then dried. Concentration
5-Meth yl-2,4-d in itr oben za m id e (19). A solution of 5.0 g
(24 mmol) of ester 14 in 50 mL of saturated anhydrous NH3 in
MeOH was stirred in a pressure reactor at 80 °C for 12 h. The
mixture was concentrated, and the resulting black residue was
purified by column chromatography eluting with EtOAc:hexanes
(1:1) to give 4.0 g (90%) of 19: mp 173-174 °C: 1H NMR (Me2-
SO-d6) δ 8.63 (s, 1H), 8.25 (s, exchanges D2O, 1H), 7.93 (s,
exchanges D2O, 1H), 7.81 (s, 1H), and 2.63 (s, 3H); 13C NMR
(Me2SO-d6) δ 165.7, 148.1, 144.3, 139.1, 136.0, 133.2, 120.6, 19.3;
CIMS m/ z (relative intensity) 226 (MH+, 38), 209 (100). Anal.
Calcd for C8H7N3O5: C, 42.68; H, 3.13; N, 18.66. Found: C,
42.74 H, 3.15; N, 18.43.
N-[(Dim eth yla m in o)m eth ylen e]- (E)-5-[2-(d im eth yla m i-
n o)eth en yl]-2,4-d in itr oben za m id e (20). A solution of 2.25
g (10 mmol) of benzamide 19 in 10 mL of DMF was treated with
6.2 mL (30 mmol) of (tert-butyloxy)bis(dimethylamino)methane.
The reaction mixture was stirred at 25 °C for 1 h. The solvent
was evaporated in vacuo, and the residue was suspended in H2O.
The precipitate was collected then washed successively with H2O
and Et2O to afford 2.76 g (84%) of 20 as a red solid: mp 218-
219 °C; 1H NMR (Me2SO-d6) δ 8.55 (s, 1H), 8.47 (s, 1H), 8.04 (d,
J ) 13.0 Hz, 1H), 7.76 (1H, s), 5.95 (d, J )13.0 Hz, 1H), 3.21 (s,
3H), 3.00 (m, 9H); 13C NMR (Me2SO-d6) 176.0, 160.5, 151.5,
141.6, 139.0, 138.9, 137.1, 123.3, 122.1, 88.9, 40.9, 35.0; CIMS
m/ z (relative intensity) 336 (MH+, 43), 335 (12). Anal. Calcd
for C14H17N5O5: C, 50.15; H, 5.11; N, 20.89. Found: C, 50.16;
H, 4.94; N 20.59.
(E )-5-[2-(D im e t h y la m in o )e t h e n y l]-2,4-d in it r o b e n z-
a m id e (21). A suspension of 13.0 g (38.8 mmol) of benzamide
20, 500 mL of MeOH, and 2.5 mL of glacial HOAc was heated
at reflux for 2 d. The hot mixture was filtered, the filtrate was
cooled slowly to 25 °C, and then the precipitated solid was
collected. Two additional crops were collected by concentrating

1158 J . Org. Chem., Vol. 61, No. 3, 1996
Notes
each respective mother liquor to a solid followed by crystalliza-
tion from MeOH. A total of 8.7 g (80%) of 21: mp 254-255 °C,
was collected: 1H NMR (Me2SO-d6) δ 8.54 (s, 1H), 8.14 (d, J )
12.8 Hz, 1H), 7.99 (br s, exchanges with D2O, 1H), 7.76 (s, 1H),
7.71 (br s, exchanges with D2O, 1H), 5.93 (d, J ) 13.0 Hz, 1H);
13C NMR (Me2SO-d6) δ 167.7, 152.6, 142.4, 139.6, 137.0, 136.5,
124.1, 122.8, 89.4; CIMS m/ z (relative intensity) 281 (MH+, 34),
280 (20), 264 (100). Anal. Calcd for C11H12N4O5: C, 47.15; H,
4.32; N 19.99. Found: C, 47.11; H, 4.25; N, 19.62.
6-Am in o-1H-in d ole-5-ca r boxa m id e (22). A mixture of 1.9
g (6.8 mmol) of enamine 21, 0.96 g of 10% Pd/C, and 190 mL of
THF was hydrogenated at 1 atm for 12 h. The mixture was
filtered, and the filtrate was concentrated to a solid that was
triturated in acetone/ether to afford 0.86 g (72%) of 22, mp 234-
235 °C dec, as an off-white solid. An analytical sample gave
mp 239-240 °C dec: 1H NMR (Me2SO-d6) δ 10.57 (s, exchanges
with D2O, 1H), 7.76 (s, 1H), 7.67 (br s, exchanges with D2O, 1H),
7.06-7.03 (m, 1H; collapses to d, J ) 3.1 Hz with D2O), 6.88 (br
s, exchanges with D2O, 1H), 6.56 (s, 1H), 6.22 (d, J ) 3.2 Hz,
1H), 6.07 (s, exchanges with D2O, 2H); CIMS m/ z (relative
intensity) 175 (M+, 58), 159 (100), 158 (71). Anal. Calcd for
C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.52; H, 5.35;
N 23.59.
over 10 min 2.3 g (34 mmol) of fuming HNO3. The resulting
suspension was stirred at 25 °C for 10 min, and then 7.1 g (34
mmol) of ester 24 was added portionwise. The mixture was
stirred at 25 °C for 20 h and then poured carefully into stirring
ice cold H2O. The aqueous phase was separated and further
extracted with CH2Cl2. The combined organic extracts were
washed with 1% aq NaOH until the aqueous phase remained
basic and then with H2O, dried, and concentrated to a yellow
oil. Column chromatography eluting with hexanes:EtOAc (8:1)
afforded 2.7 g (31%) of 25 as a solid, mp 58-59 °C (lit.13 mp
58-59 °C): 1H NMR (Me2SO-d6) δ 8.30 (d, J ) 8.5 Hz, 1H), 7.86
(d, J ) 8.5 Hz, 1H), 4.29 (q, J ) 7.1 Hz, 2H), 2.43 (s, 3H), 1.20
(t, J ) 7.1 Hz, 3H); 13C NMR (Me2SO-d6) δ 162.4, 148.2, 145.1,
138.7, 135.6, 127.9, 123.2, 63.8, 18.4, 13.8; CIMS m/ z (relative
intensity) 254 (M+, 4.6), 209 (100). Anal. Calcd for
C10H10N2O6: C, 47.25; H, 3.97; N, 11.02. Found: C, 47.31; H,
3.98; N, 11.00. Further workup afforded 2.6 g (30%) of isomeric
compound 14.
(E )-3-[2-(Dim e t h yla m in o)e t h e n yl]-2,6-d in it r ob e n zoic
Acid , Eth yl Ester (26). A mixture of 1.1 g (4.9 mmol) of ester
25, 1.3 mL (9.7 mmol) of DMF dimethyl acetal, and 5 mL of DMF
was heated at 100 °C for 4 h. The solution was cooled and
poured into H2O, and the precipitated red solid was collected.
The solid was washed with H2O and dried to afford 1.2 g (70%)
of 26: mp 174-175 °C: 1H NMR (Me2SO-d6) δ 7.95 (d, J ) 9.3
Hz, 1H), 7.87 (d, J ) 12.7 Hz, 1H), 7.78 (d, J ) 9.3 Hz, 1H), 4.92
(d, J ) 12.7 Hz, 1H), 4.23 (q, J ) 7.1 Hz, 2H), 2.90 (br s, 6H),
1.19 (t, J ) 7.1 Hz, 3H); 13C NMR (Me2SO-d6) δ 163.4, 151.4,
141.4, 141.3, 136.7, 126.7, 125.7, 123.2, 86.3, 63.1, 13.8; CIMS
m/ z (relative intensity) 310 (MH+, 81), 309 (32). Anal. Calcd
for C13H15N3O6: C, 50.49; H, 4.89; N, 13.59. Found: C, 50.94;
H, 4.93; N, 13.51.
1,6-Dih yd r o-5H -p yr r olo[3,2-g]q u in a zolin -5-on e
(3).
Meth od A. A solution of 10.3 g (50 mmol) of the aminoindole
17 and 6.3 g (60 mmol) of formamidine acetate in 200 mL of
2-methoxyethanol was heated at reflux for 2 h and then
concentrated to dryness. The residue was slurried in H2O and
filtered to afford crude 3. The solid was dissolved in excess 1 N
aq NaOH, and the solution was filtered and then brought to
neutrality with 3 N aq HCl. The solid was collected and dried
to give 6.0 g (64%) of 3: mp 347 °C dec: 1H NMR (Me2SO-d6) δ
11.75 (br s, exchanges with D2O, 1H), 11.49 (br s, exchanges
with D2O, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.62 (dd,
J ) 3.0, 2.4 Hz), 6.68 (dd, J ) 3.0, 0.9 Hz); 13C NMR δ 161.7,
143.0, 142.2, 140.0, 129.4, 127.8, 117.6, 115.5, 107.2, 102.1; CIMS
m/ z (relative intensity) 186 (MH+, 100), 185 (61). Anal. Calcd
for C10H7N3O: C, 64.86; H, 3.81; N, 22.69. Found: C, 64.57; H,
3.64; N, 22.66.
Meth od B. A suspension of 0.25 g (1.4 mmol) of indole amide
22 and 7 mL of triethyl orthoformate was heated at 100 °C for
1 h. The mixture was cooled to 25 °C and filtered, and the
filtrate was concentrated to a solid that was triturated in hot
EtOAc. The solids were collected and dried to leave 0.13 g (50%)
of pure 3, mp > 280 °C, identical with material obtained by
method A.
Meth od C. A mixture of 0.6 g (1.8 mmol) of 20 and 0.2 g of
Raney nickel in 50 mL of 1:1 THF:MeOH was hydrogenated in
a rocking autoclave at 1500 psi at 25 °C for 22 h. The catalyst
was filtered, and the filtrate was concentrated. The crude solid
was triturated in i-PrOH, collected, washed with i-PrOH and
Et2O, and then dried to leave 0.19 g (57%) of 3, mp > 280 °C,
shown to contain minor impurities by 1H NMR.
5-Meth yl-2-n itr oben zoic Acid , Eth yl Ester (24). A solu-
tion of 99 g (0.54 mol) of acid 23, 1 L of EtOH, and 70 g of concd
H2SO4 was heated at reflux for 2 d. The solution was concen-
trated, and the resultant oil was diluted with 300 mL of EtOAc.
The organic phase was washed with 1% aq NaOH until the
aqueous phase remained basic, dried, and concentrated in vacuo
at 40 °C overnight to afford 103 g (91%) of 24 as a yellow oil:
1H NMR (Me2SO-d6) δ 7.89 (d, J ) 8.2 Hz, 1H), 7.64 (s, 1H),
7.60 (d, J ) 8.2 Hz, 1H), 4.31 (q, J ) 7.0 Hz, 2H), 2.45 (s, 3H),
1.27 (t, J ) 7.0 Hz, 3H); 13C NMR (Me2SO-d6) δ 165.1, 145.0,
132.6, 129.8, 127.2, 124.2, 62.0, 20.7, 13.7; CIMS m/ z (relative
intensity) 210 (MH+, 3), 164 (100). Anal. Calcd for C10H11NO4:
C, 57.41; H, 5.30; N, 6.70. Found: C, 57.46; H, 5.34; N, 6.55.
2,6-Din itr o-m -tolu ic Acid , Eth yl Ester (25). To a solution
of 9.7 g (64 mmol) of CF3SO3H in 20 mL of CH2Cl2 was added
6-Am in o-1H-in d ole-7-ca r boxylic Acid , Eth yl Ester (27).
A mixture of 1.1 g (3.5 mmol) of enamine 26, 0.5 g of 10% Pd/C,
and 100 mL of MeOH was hydrogenated at 50 psi for 4 h. The
mixture was filtered, concentrated, and then purified by column
chromatography eluting with 4:1 hexanes:EtOAc. The product
fractions were concentrated to a solid that was triturated from
hexanes to afford 0.35 g (48%) of 27: mp 81-82 °C: 1H NMR
(Me2SO-d6) δ 10.3 (br s, exchanges with D2O, 1H), 7.39 (d, J )
8.6 Hz, 1H), 6.95 (m, 1H), 6.63 (s, exchanges with D2O, 2H), 6.45
(dd, J ) 8.7, 2.4 Hz, 1H), 6.23 (m, 1H), 4.36 (q, J ) 7.3 Hz, 2H),
1.31 (t, J ) 7.3 Hz, 3H); 13C NMR (Me2SO-d6) δ 168.1, 149.9,
135.0, 127.8, 122.2, 119.0, 110.7, 102.4, 94.0, 60.0, 15.1; CIMS
m/ z (relative intensity) 204 (M+, 100). Anal. Calcd for
C
11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.66; H,
5.98; N, 13.64.
1,6-Dih yd r o-9H-p yr r olo[2,3-f]qu in a zolin -9-on e (4). A so-
lution of 0.10 g (0.49 mmol) of indole 27 in 2 mL of formamide
was heated for 1 h each at 130 °C, 150 °C, and 180 °C. The
mixture was cooled and poured into ice-cold H2O. The aqueous
suspension was extracted with EtOAc, and the organic layer was
washed with brine, dried, and concentrated. Purification of the
oily residue by column chromatography eluting with 9:1 CH2-
Cl2:MeOH gave a solid that was crystallized from ca. 2:1 EtOAc:
hexanes to provide 0.042 g (44%) of 4: mp 297-298 °C; 1H NMR
(Me2SO-d6) δ 12.3 (br s, exchanges with D2O, 1H), 11.5 (br s,
exchanges with D2O, 1H), 8.03 (s, 1H), 7.95 (d, J ) 8.3 Hz, 1H),
7.38 (dd, J ) 3.0, 2.6 Hz, 1H), 7.27 (d, J ) 8.3 Hz, 1H), 6.59 (dd,
J ) 3.0, 2.2 Hz, 1H); 13C NMR (Me2SO-d6) δ 160.8, 145.5, 142.9,
130.8, 127.3, 126.7, 125.6, 118.0, 107.9, 102.1; CIMS m/ z
(relative intensity) 186 (MH+, 96), 185 (100). Anal. Calcd for
C
10H7N3O: C, 64.86; H, 3.81; N, 22.69. Found: C, 64.59; H, 3.79;
N, 22.59.
J O951790B