1, 2, 3, 9-tetrahydro-4H-carbazol-4-one and 8, 9-dihydropyrido- [1, 2-a]indol-6(7H)-one from 1H-indole-2-butanoic acid

Article abstract of DOI:10.1002/jhet.22

Efficient syntheses of the title ring systems have been developed from 1H-indole-2-butanoic acid, which was easily prepared from 2-fluoro-1- nitrobenzene in four steps. Heating 1H-indole-2-butanoic acid in toluene containing p-toluenesulfonic acid at 110°

Full text of DOI:10.1002/jhet.22

172
1,2,3,9-Tetrahydro-4H-carbazol-4-one and 8,9-Dihydropyrido-
[1,2-a]indol-6(7H)-one from 1H-Indole-2-butanoic Acid
Vol 46
Richard A. Bunce* and Baskar Nammalwar
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received July 9, 2008
DOI 10.1002/jhet.22
Published online 20 March 2009 in Wiley InterScience (www.interscience.wiley.com).
Efficient syntheses of the title ring systems have been developed from 1H-indole-2-butanoic acid,
which was easily prepared from 2-fluoro-1-nitrobenzene in four steps. Heating 1H-indole-2-butanoic
acid in toluene containing p-toluenesulfonic acid at 110ꢀC furnished 1,2,3,9-tetrahydro-4H-carbazol-4-
one in 88% yield. Heating this same acid in toluene with no added acid gave 8,9-dihydropyrido[1,2-a]-
indol-6(7H)-one in 90% yield. The tetrahydro-4H-carbazol-4-one was also prepared directly in 92%
yield from methyl 6-(2-nitrophenyl)-5-oxohexanoate by a tandem reduction—cycloaromatization—acyl-
ation reaction with iron in concentrated hydrochloric acid at 110ꢀC. Application of this approach to the
closure of five- and seven-membered rings was also successful.
J. Heterocyclic Chem., 46, 172 (2009).
INTRODUCTION
pling reactions [15]. Our synthesis requires several steps,
but permits the preparation of two pharmacologically val-
uable compounds without excessively hazardous reagents
or expensive catalysts. We have also found that other sat-
urated ring homologues of the title compounds are avail-
able using this strategy.
Earlier studies from this laboratory [1] and by others
[2] described the synthesis of substituted indoles from
2-nitrobenzyl ketones based on a tandem reduction—
cycloaromatization reaction. Our recent work has sought
to assemble more complex structures using this strategy.
In this study, we have developed a route to synthesize
1,2,3,9-tetrahydro-4H-carbazol-4-one and 8,9-dihydro-
pyrido[1,2-a]indol-6(7H)-one from 1H-indole-2-butanoic
acid. In the course of this study, we also discovered that
the tetrahydro-4H-carbazol-4-one could be prepared
from methyl 6-(2-nitrophenyl)-5-oxohexanoate in one
step by a tandem reduction—cycloaromatization—acyla-
tion sequence. Tetrahydro-4H-carbazol-4-one is an im-
portant building block for the synthesis of alkaloids [3]
as well as the core ring structure in current drugs used
for the treatment of cancer [4], HIV [5], congestive
heart failure [6], and emesis resulting from chemother-
apy [7]; 8,9-dihydropyrido[1,2-a]indol-6(7H)-ones have
been studied for the treatment of ischemic disorders [8]
and vomiting caused by cancer treatment [9].
RESULTS AND DISCUSSION
Our cyclization studies required access to a series of
1H-indole-2-alkanecarboxylic acids. To this end, a syn-
thesis of these precursors was devised and carried out
from Meldrum’s acid [16] and commercially available
(x-chlorocarbonyl)alkanoic esters 1a–c (Scheme 1).
Acylation of Meldrum’s acid with 1a–c in the presence
of pyridine followed by refluxing in tert-butyl alcohol
gave the tert-butyl methyl 3-oxoalkanedicarboxylic
esters 2a-c in 68–76% yields [17]. Deprotonation of 2a–
c with sodium hydride in anhydrous N,N-dimethylforma-
mide and reaction with 2-fluoro-1-nitrobenzene at 55–
60ꢀC afforded the nucleophilic aromatic substitution
products 3a–c in yields ranging from 69 to 71% [1,2].
Subsequent exposure of 3a–c to trifluoroacetic acid in
the presence of triethylsilane [18] resulted in tert-butyl
ester cleavage and decarboxylation to provide nitro
ketoesters 4a–c in 92–94% yields. Treatment of 4a-c
with iron powder in acetic acid then initiated a tandem
reduction—cycloaromatization reaction to furnish 1H-
indole-2-alkanecarboxylic esters 5a–c in 90–95% yields
[1]. Finally, basic hydrolysis of 5a–c provided acids 6a–
c in 90–96% yields.
Several other approaches have been reported for the tet-
rahydro-4H-carbazol-4-one system. The Fischer indole
synthesis between phenylhydrazine and 1,3-cyclohexane-
dione is the simplest, but only provides a 50% yield [10].
Other routes include C4 oxidation of tetrahydrocarbazole
[11]; base-promoted cyclization of 2-(2-trifluoroacetami-
dophenyl)-2-cyclohexen-1-one [12]; copper(I)-mediated
[13] or photochemical [14] arylation of N-substituted
enaminones; and a number of palladium-catalyzed cou-
C
V
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1,2,3,9-Tetrahydro-4H-carbazol-4-one and 8,9-Dihydropyrido-[1,2-a]indol-6(7H)-one
173
Scheme 1 [a]
Scheme 3
ꢁ80% yields, however, using N-(3-dimethylamino-
propyl)-N0-ethylcarbodiimide hydrochloride [19] in the
presence of 1.6 equivalents of 4-(dimethylamino)pyridine
[20]. Numerous other ring-closing regimes [21] failed to
give the desired lactams. This seems to be the first report
describing the use of N-(3-dimethylaminopropyl)-N0-eth-
ylcarbodiimide with 4-(dimethylamino)pyridine for lac-
tam closures. The function of the base in this reaction is
two-fold, neutralizing the hydrochloride salt of the carbo-
diimide and scavenging a proton from the cyclized amide.
Remarkably, it was found that treatment of 4b with
iron in concentrated hydrochloric acid yielded 7b in
92% yield by a tandem process involving a reduction—
cycloaromatization—acylation sequence. Attempts to
cyclize 6a and 6c under the same conditions afforded
significantly lower yields and the product mixtures were
more complex. The one-step conversion of 4b to 7b rep-
resents a new tandem reaction sequence.
The results of our cyclization studies are summarized
in Scheme 2. Treatment of 6a–c with 2.0–6.0 equivalents
of p-toluenesulfonic acid in refluxing toluene resulted in a
Friedel-Crafts-like ring closure of the acid to C3 of the
indole moiety to yield 7a–c in 72–88% yields. Refluxing
6b in toluene without the added p-toluenesulfonic acid
resulted in closure to lactam 8b (90%); acids 6a and 6c
did not cyclize under these conditions reflecting stereo-
electronic problems in closing the five- and seven-mem-
bered rings. Lactamization of 6a and 6c was possible in
Mechanistically, reduction of the aromatic nitro group
is followed by cycloaromatization to the indole system
as previously observed [1,2]. Under strong acid condi-
tions, however, the methyl ester is cyclized onto the C3
position of indole. This most likely occurs by protona-
tion of the ester carbonyl, addition of the electron-rich
indole double bond to the carbonyl carbon, loss of meth-
anol and rearomatization (Scheme 3). The closure of
acids 6a and 6c–7a and 7c should be analogous to the
conversion of 10 to 7b with loss of water in the penulti-
mate step. Finally, the lactamization reactions proceed
via the expected cyclocondensation mechanisms, with
and without added carbodiimide.
Scheme 2 [a]
CONCLUSION
We have developed a new approach to the synthesis of
the title compounds using 1H-indole-2-butanoic acid (6b)
as a common intermediate. Heating this acid in refluxing
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

174
R. A. Bunce and B. Nammalwar
Vol 46
some enol as a colorless oil, bp 85–110ꢀC (0.5 mmHg). IR:
toluene containing p-toluenesulfonic acid affords 1,2,3,9-
tetrahydro-4H-carbazol-4-one (7b), while heating in tolu-
ene with no added acid yields 8,9-dihydropyrido[1,2-
a]indol-6(7H)-one (8b). A high yield of 7b can also be
achieved directly from 4b via a tandem reduction—cyclo-
aromatization—acylation reaction promoted by iron in
concentrated hydrochloric acid. Homologues 7a and 7c
can also be prepared by heating 6a and 6c in toluene with
p-toluenesulfonic acid, but direct conversion from 4a and
4c with iron in concentrated hydrochloric acid was unsuc-
cessful. Lactamization of 6a and 6c requires treatment
1
1737, 1717 cmꢂ1; H NMR: d 3.68 (s, 3H), 3.41 (s, 2H), 2.87
(t, 2H, J ¼ 6.6), 2.62 (t, 2H, J ¼ 6.6), 1.47 (s, 9H); 13C NMR:
d 201.4, 172.8, 166.2, 81.9, 51.7, 50.4, 37.2, 27.8 (3C), 27.5.
tert-Butyl methyl 3-oxoheptanedioate (2b). This compound
(9.00 g, 76% containing some enol) was isolated as a colorless
oil, bp 110–130ꢀC (0.5 mmHg). IR: 1738, 1716 cmꢂ1 1H
;
NMR: d 3.67 (s, 3H), 3.35 (s, 2H), 2.62 (t, 2H, J ¼ 7.0), 2.36
(t, 2H, J ¼ 7.2), 1.92 (quintet, 2H, J ¼ 7.1), 1.47 (s, 9H); 13C
NMR: d 202.5, 173.5, 166.4, 82.0, 51.5, 50.5, 41.6, 32.7, 27.9
(3C), 18.5.
tert-Butyl methyl 3-oxooctanedioate (2c). This compound
(8.50 g, 68% containing some enol) was isolated as a colorless
oil, bp 125–140ꢀC (0.5 mmHg). IR: 1735, 1716 cmꢂ1 1H
;
with
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride in the presence of excess 4-(dimethylami-
no)pyridine. The synthesis requires several steps, but pro-
vides a number of pharmacologically useful compounds
in high yield without excessively hazardous or expensive
reagents.
NMR: d 3.67 (s, 3H), 3.35 (s, 2H), 2.56 (distorted t, 2H, J ¼
6.7), 2.33 (distorted t, 2H, J ¼ 6.7), 1.63 (m, 4H), 1.47 (s,
9H); 13C NMR: d 202.8, 173.7, 166.4, 81.9, 51.5, 50.5, 42.3,
33.7, 27.9 (3C), 24.2, 22.7.
Representative procedure for nucleophilic aromatic sub-
stitution: tert-butyl methyl 2-(2-nitrophenyl)-3-oxohexane-
dioate (3a). A modification of the procedure described by
Bunce et al. was used [1]. To a suspension of 1.36 g (56.7
mmoles) of oil-free sodium hydride in 20 mL of dry N,N-dime-
thylformamide was added 4.00 g (28.4 mmoles) of 2-fluoro-1-
nitrobenzene in 25 mL of dimethylformamide. Stirring was initi-
ated and a solution of 6.35 g (29.7 mmoles) of 2a in 5 mL of
dimethylformamide was added. The reaction mixture was heated
to 55–60ꢀC and stirred for 48 h, then cooled, added to 50 mL of
saturated ammonium chloride and extracted with ether (three
times). The combined organic extracts were washed with satu-
rated sodium chloride (one time), dried (magnesium sulfate) and
concentrated under vacuum. The crude product was purified by
flash chromatography on a 50 cm ꢃ 2 cm silica gel column
using 10% ether in hexanes to give 6.65 g (69%) of keto diester
3a containing some enol as a yellow oil. IR: 1736, 1640, 1613,
EXPERIMENTAL
The commercial acid chlorides were used as received. N,N-
Dimethylformamide, from a freshly opened bottle, was dried
˚
over 4 A molecular sieves under nitrogen and transferred by sy-
ringe into reactions where it was used. The hydrochloric acid
(1M, 2M, and 6M), sodium hydroxide (1M), ammonium chloride
(saturated), sodium bicarbonate (saturated), and sodium chloride
(saturated) employed in various procedures refer to aqueous sol-
utions. All reactions were run under N2 in oven-dried glassware.
Reactions were monitored by thin layer chromatography on
silica gel GF plates (Analtech 21521). Preparative separations
were performed using flash column chromatography [22] on
silica gel (grade 62, 60–200 mesh) mixed with ultraviolet-active
phosphor (Sorbent Technologies UV-5) or thin layer chromatog-
raphy on 20 cm x 20 cm silica gel GF plates (Analtech 02015).
Band elution, for both methods, was monitored using a hand-
held ultraviolet lamp. Hexanes used in chromatography had a
boiling range of 65–70ꢀC. Melting points were uncorrected.
Infrared spectra were run as thin films on sodium chloride disks
and were referenced to polystyrene. Unless otherwise indicated,
1H and 13C nuclear magnetic resonance spectra were measured
in chloroform-d1 at 300 MHz and 75 MHz, respectively, and
were referenced to internal tetramethylsilane; coupling constants
(J) are reported in Hertz. Low-resolution mass spectra (electron
impact/direct probe) were run at 70 electron volts.
Representative procedure for the preparation of tert-butyl
methyl 3-oxoalkanedicarboxylic esters: tert-butyl methyl 3-
oxohexanedioate (2a). The procedure of Yonemitsu and co-
workers was used [18]. To a stirred solution of 7.00 g (48.6
mmoles) of Meldrum’s acid and 7.68 g (97.2 mmoles) of pyri-
dine in 50 mL of dichloromethane at 0ꢀC was added a solution
of 7.68 g (51.0 mmoles) of 1a in 10 mL of dichloromethane.
Stirring was continued at 0ꢀC for 30 min and at 22ꢀC for 1 h.
The crude reaction mixture was washed with 2M hydrochloric
acid (three times) to remove the excess pyridine and the solu-
tion was dried (magnesium sulfate) and concentrated under
vacuum. The resulting oil was dissolved in 50 mL of tert-butyl
alcohol and refluxed for 3 h. The crude reaction mixture was
cooled, concentrated under vacuum and distilled under high
vacuum to give 8.20 g (73%) of keto diester 2a containing
1
1520, 1351 cmꢂ1; H NMR: d 7.98 (dd, 1H, J ¼ 8.0, 1.2), 7.58
(td, 1H, J ¼ 7.6, 1.4), 7.46 (td, 1H, J ¼ 7.9, 1.6), 7.33 (dd, 1H,
J ¼ 7.6, 1.4), 5.28 (s, 1H), 3.64 (s, 3H), 2.50 (m, 4H), 1.32 (s,
9H); 13C NMR: d 200.4, 172.7, 170.6, 149.7, 133.7, 132.6,
130.1, 128.3, 124.5, 82.6, 61.3, 51.7, 37.4, 29.8, 27.8 (3C).
tert-Butyl methyl 2-(2-nitrophenyl)-3-oxoheptanedioate
(3b). This compound (6.00 g, 69% containing some enol) was
isolated as a yellow oil. IR: 1738, 1645, 1526, 1394, 1352 cmꢂ1
;
1H NMR: d 7.98 (dd, 1H, J ¼ 8.0, 1.2), 7.57 (td, 1H, J ¼ 7.6,
1.4), 7.45 (td, 1H, J ¼ 7.9, 1.4), 7.25 (dd, 1H, J ¼ 7.6, 1.4), 5.25
(s, 1H), 3.57 (s, 3H), 2.25 (m, 4H), 1.88 (m, 2H), 1.33 (s, 9H);
13C NMR: d 200.8, 172.7, 170.7, 149.7, 133.7, 132.8, 130.1,
128.4, 124.3, 82.6, 61.3, 51.8, 37.4, 29.9, 28.0, 27.8 (3C).
tert-Butyl methyl 2-(2-nitrophenyl)-3-oxooctanedioate
(3c). This compound (4.20 g, 71% containing some enol) was
isolated as a yellow oil. IR: 1735, 1643, 1615, 1524, 1352 cmꢂ1
;
1H NMR: d 7.98 (dd, 1H, J ¼ 8.0, 1.3), 7.56 (td, 1H, J ¼ 7.5,
1.4), 7.45 (td, 1H, J ¼ 7.9, 1.6). 7.25 (dd, 1H, J ¼ 7.7. 1.4), 5.26
(s, 1H), 3.63 (s, 3H), 2.21 (m, 2H), 2,12 (m, 2H), 1.57 (m, 4H),
1.24 (s, 9H); 13C NMR: d 201.8, 173.7, 170.7, 149.7, 133.7,
132.5, 130.5, 128.8, 124.3, 82.4, 61.0, 51.5, 33.6, 32.5, 27.8
(3C), 25.7, 24.3.
Representative procedure for tert-butyl ester cleavage and
decarboxylation: methyl 5-(2-nitrophenyl)-4-oxopentanoate
(4a). The procedure of Mehta et al. [17] was used. To a solu-
tion of 5.20 g (14.8 mmoles) of 3a in 50 mL of dichlorome-
thane were added 27.6
g (18.0 mL, 242 mmoles) of
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1,2,3,9-Tetrahydro-4H-carbazol-4-one and 8,9-Dihydropyrido-[1,2-a]indol-6(7H)-one
175
trifluoroacetic acid and 4.88 g (6.70 mL, 42.0 mmoles) of tri-
ethylsilane. The mixture was stirred at 22ꢀC for 1 h and then
concentrated under vacuum to give 3.50 g (94%) of 4a as a
light yellow oil, which was used without further purification.
2.04 (m, 2H); 13C NMR: d 173.9, 138.4, 128.8, 121.1,
119.8, 119.6, 110.3, 100.0, 51.6, 33.1, 30.0, 27.3, 24.5; ms:
m/z 217 (Mþ). Anal. Calcd. for C13H15NO2: C, 71.89; H,
6.91; N, 6.45. Found: C, 71.85; H, 6.92; N, 6.43.
Methyl 1H-indole-2-pentanoate (5c). This compound (1.10
g, 90%) was isolated as a tan solid, mp 121–124ꢀC. IR: 3353,
1719 cmꢂ1; 1H NMR: d 7.98 (br s, 1H), 7.52 (d, 1H, J ¼ 6.8 Hz),
7.28 (d, 1H, J ¼ 8.0 Hz), 7.08 (m, 2H), 6.24 (s, 1H), 3.67
(s, 3H), 2.76 (t, 2H, J ¼ 7.2 Hz), 2.37 (t, 2H, J ¼ 3.6 Hz),
1.76 (m, 4H); 13C NMR: d 174.2, 139.3, 136.0, 128.9,
121.2, 119.6, 119.8, 110.5, 99.8, 51.7, 33.9, 28.7, 28.0, 24.6;
ms: m/z 231 (Mþ). Anal. Calcd. for C14H17NO2: C, 72.73;
H, 7.36; N, 6.06. Found: C, 72.70; H, 7.33; N, 6.10.
IR: 1735, 1722, 1525, 1351 cmꢂ1
;
1H NMR: d 8.11 (dd, 1H,
J ¼ 8.0, 1.1), 7.60 (td, 1H, J ¼ 7.7, 1.3), 7.46 (td, 1H, J ¼
7.9, 1.5), 7.31 (dd, 1H, J ¼ 7.7, 1.1), 4.16 (s, 2H), 3.67 (s,
3H), 2.93 (t, 2H, J ¼ 6.5), 2.65 (t, 2H, J ¼ 6.5); 13C NMR: d
204.0, 173.1, 148.5, 133.7, 133.6, 130.1, 128.5, 125.2, 51.8,
47.8, 37.1, 27.8; ms: m/z 251 (Mþ). Anal. Calcd. for
C12H13NO5: C, 57.37; H, 5.18; N, 5.58. Found: C, 57.41; H,
5.21; N, 5.53.
Methyl 6-(2-nitrophenyl)-5-oxohexanoate (4b). This com-
pound (3.46 g, 92%) was isolated as a light yellow oil and
Representative procedure for the ester hydrolysis: 1H-
indole-2-propanoic acid (6a). A mixture of 1.00 g (4.93
mmoles) of 5a in 20 mL of dioxane and 15 mL of 1M sodium
hydroxide was stirred at 22ꢀC for 1 h. The solution was con-
centrated to one-half volume under vacuum, acidified with 3M
hydrochloric acid and extracted with ether (three times). The
combined ether layers were washed with saturated sodium
chloride (one time), then dried (magnesium sulfate) and con-
centrated under vacuum. The crude product was purified by
flash chromatography on a 15 cm ꢃ 2 cm silica gel column
using 50% ether in hexanes to give 0.85 g (91%) of 6a as a
white solid, mp 165–167ꢀC (lit [24] mp 167ꢀC). IR: 3462–
used without further purification. IR: 1729, 1525, 1346 cmꢂ1
;
1H NMR: d 8.11 (dd, 1H, J ¼ 8.0, 1.1), 7.59 (td, 1H, J ¼ 7.7,
1.5), 7.46 (td, 1H, J ¼ 7.9, 1.5), 7.28 (dd, 1H, J ¼ 7.7, 1.1),
4.09 (s, 2H), 3.68 (s, 3H), 2.70 (t, 2H, J ¼ 7.1), 2.38 (t, 2H,
J ¼ 7.1), 1.96 (quintet, 2H, J ¼ 7.1); 13C NMR: d 204.9,
173.6, 148.6, 133.6 (2C), 130.2, 128.4, 125.2, 51.6, 47.9, 41.4,
32.9, 18.7; ms: m/z 265 (Mþ). Anal. Calcd. for C13H15NO5: C,
58.87; H, 5.66; N, 5.28. Found: C, 59.00: H, 5.58; N, 5.23.
Methyl 7-(2-nitrophenyl)-6-oxoheptanoate (4c). This com-
pound (1.45 g, 92%) was isolated as a light yellow oil and
used without further purification. IR: 1727, 1528, 1352 cmꢂ1
;
1H NMR: d 8.10 (dd, 1H, J ¼ 8.2, 1.3), 7.59 (td, 1H, J ¼ 7.5,
1.3), 7.46 (td, 1H, J ¼ 8.1, 1.5), 7.27 (dd, 1H, J ¼ 7.6, 1.1),
4.10 (s, 2H), 3.67 (s, 3H), 2.62 (distorted t, 2H, J ¼ 6.8), 2.34
(distorted t, 2H, J ¼ 6.8), 1.67 (m, 4H); 13C NMR: d 205.2,
173.8, 148.6, 133.5 (2C), 130.3, 128.3, 125.2, 51.5, 47.8, 42.2,
33.7, 24.3, 22.9; ms: m/z 279 (Mþ). Anal. Calcd. for
C14H17NO5: C, 60.22; H, 6.09; N, 5.02. Found: C, 60.24; H,
6.10; N, 4.98.
2300, 3392, 1701 cmꢂ1 1H NMR: d 9.87 (br s, 1H), 8.26
;
(br s, 1H), 7.52 (dd, 1H, J ¼ 7.7, 0.7), 7.30 (dd, 1H, J ¼ 8.0,
0.9), 7.13 (td, 1H, J ¼ 7.7, 1.3), 7.07 (td, 1H, J ¼ 7.9, 1.1),
6.26 (dd, 1H, J ¼ 1.9, 0.8), 3.08 (t, 2H, J ¼ 6.8), 2.81 (t, 2H,
J ¼ 6.8); 13C NMR: d 178.4, 137.6, 135.5, 128.4, 121.4,
119.9, 119.7, 110.5, 99.9, 33.6, 22.9; ms: m/z 189 (Mþ). Anal.
Calcd. for C11H11NO2: C, 69.84; H, 5.82; N, 7.41. Found: C,
69.88; H, 5.85; N, 7.37.
Representative procedure for reductive cyclization to the
1H-indoles: methyl 1H-indole-2-propanoate (5a). The proce-
dure of Bunce et al. [1] was used. A mixture of 1.50 g (5.98
mmoles) of 4a, 25 mL of acetic acid and 2.00 g (35.9 mmoles,
6.0 eq) of iron powder (>100 mesh) was heated with stirring
at 115ꢀC (oil bath) until thin layer chromatography indicated
complete consumption of starting material (ca 30 min). The
crude reaction was cooled, transferred to a separatory funnel
containing 50 mL of water and extracted with ether (three
times). The combined ether layers were washed with water
(one time), saturated sodium bicarbonate (three times), satu-
rated sodium chloride (one time), then dried (magnesium sul-
fate) and concentrated under vacuum to give a brown solid.
Recrystallization from hexanes gave 1.10 g (91%) of 5a as a
tan solid, mp 97–98ꢀC (lit [23] mp 97–98ꢀC, hexane). IR:
1H-Indole-2-butanoic acid (6b). This compound (0.33 g,
90%) was isolated as a white solid, mp 114–115ꢀC. IR: 3252–
1
2348, 3386, 1700 cmꢂ1; H NMR: 10.85 (br s, 1H), 7.95 (br s,
1H), 7.52 (dd, 1H, J ¼ 7.7, 0.7), 7.29 (dd, 1H, J ¼ 8.0, 0.9),
7.12 (td, 1H, 7.9, 1.3), 7.07 (td, 1H, J ¼ 7.7, 1.1), 6.27 (dd,
1H, J ¼ 2.0, 0.8), 2.83 (t, 2H, J ¼ 7.3), 2.45 (t, 2H, J ¼ 7.3),
2.06 (quintet, 2H, J ¼ 7.3); 13C NMR: d 179.2, 138.1, 135.9,
128.7, 121.2, 119.9, 119.7, 110.4, 100.1, 33.0, 27.3, 24.2; ms:
m/z 203 (Mþ). Anal. Calcd. for C12H13NO2: C, 70.94; H, 6.40;
N, 6.90. Found: C, 70.98; H, 6.41; N, 6.85.
1H-Indole-2-pentanoic acid (6c).. This compound (0.90 g,
96%) was isolated as a white solid, mp 145–147ꢀC. IR: 3425–
1
2350, 3384, 1700 cmꢂ1; H NMR: d 10.50 (s, 1H), 7.92 (br s,
1H), 7.52 (d, 1H, J ¼ 6.8 Hz), 7.30 (d, 1H, J ¼ 8.0 Hz), 7.10
(m, 2H), 6.24 (s, 1H), 2.80 (t, 2H, J ¼ 6.8 Hz), 2.42 (t, 2H,
J ¼ 7.2 Hz), 1.76 (m, 4H); 13C NMR: d 178.4, 138.9, 135.7,
128.7, 121.0, 119.7, 119.6, 110.2, 99.7, 33.4, 28.4, 27.8, 24.1;
ms: m/z 217 (Mþ). Anal. Calcd. for C13H15NO2: C, 71.89; H,
6.91; N, 6.45. Found: C, 71.88; H, 6.86; N, 6.47.
Representative procedure for indole acylation: 3,4-dihy-
drocyclopent[b]indol-1(2H)-one (7a). A solution of 200 mg
(1.06 mmoles) of 6a in 10 mL of toluene was heated to reflux
and 200 mg of p-toluenesulfonic acid monohydrate was slowly
added through the top of the condenser. After 1 h at reflux, a
second 200-mg portion of p-toluenesulfonic acid (total 400 mg,
2.10 mmoles, 2.0 eq) was added and refluxing was continued for
a total of 12 h. The resulting solution was cooled, added to
water and extracted with ether. The ether layer was washed
3357, 1720 cmꢂ1 1H NMR: d 8.47 (br s, 1H), 7.52 (dd, 1H,
;
J ¼ 7.9, 0.6), 7.31 (dq, 1H, J ¼ 8.0, 0.9), 7.12 (td, 1H, J ¼
7.9, 1.3), 7.06 (td, 1H, J ¼ 7.9, 1.1), 6.24 (dd, 1H, J ¼ 2.0,
0.9), 3.72 (s, 3H), 3.08 (t, 2H, J ¼ 6.7), 2.73 (t, 2H, J ¼ 6.7);
13C NMR: d 174.3, 138.1, 136.0, 128.4, 121.3, 119.9, 119.6,
110.5, 99.8, 51.9, 33.9, 23.1; ms: m/z 203 (Mþ). Anal. Calcd.
for C12H13NO2: C, 70.94; H, 6.40; N, 6.90. Found: C, 70.92;
H, 6.39; N, 6.92.
Methyl 1H-indole-2-butanoate (5b). This compound (1.15
g, 95%) was isolated as a tan solid, mp 69–71ꢀC. IR: 3392,
1718 cmꢂ1; 1H NMR: 8.06 (br s, 1H), 7.52 (d, 1H, J ¼ 7.6 Hz),
7.30 (d, 1H, J ¼ 6.0 Hz), 7.08 (m, 2H), 6.25 (s, 1H), 3.66
(s, 3H), 2.81 (t, 2H, J ¼ 7.2 Hz), 2.40 (t, 2H, J ¼ 7.2 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

176
R. A. Bunce and B. Nammalwar
Vol 46
with saturated sodium bicarbonate (three times) and saturated
sodium chloride (one time), then dried (magnesium sulfate)
and concentrated under vacuum. The crude product was
purified by flash chromatography on a 20 cm ꢃ 2 cm silica
gel column using increasing concentrations of ether in hex-
anes to give 136 mg (75%) of 7a as an off-white solid, mp
Representative procedures for lactam formation: 1,2-
dihydro-3H-pyrrolo[1,2-a]indol-3-one (8a). To a suspension
of 100 mg (0.53 mmoles) of 6a in 5 mL of dichloromethane
was added 103 mg (0.85 mmoles, 1.6 eq) of 4-(dimethylami-
no)pyridine. The mixture was stirred for 10 min to give a clear
light brown solution. To this solution was added 101 mg (0.53
mmoles) of N-(3-dimethylaminopropyl-N0-ethylcarbodiimide
hydrochloride and the reaction mixture was stirred at 22ꢀC for
24 h. The crude reaction mixture was washed with water, 1M
hydrochloric acid, saturated sodium bicarbonate and saturated
sodium chloride, then dried (magnesium sulfate) and concen-
trated under vacuum. The resulting oil was purified by prepar-
ative thin layer chromatography using 60% ether in hexanes to
give 72 mg (80%) of the lactam as a white ꢂs1olid, mp 149–
250–252ꢀC (lit [11] mp 252–253ꢀC). IR: 3371, 1648 cmꢂ1
;
1H NMR (dimethyl sulfoxide-d6): d 12.0 (br s, 1H), 7.67 (d,
1H, J ¼ 7.5), 7.45 (d, 1H, J ¼ 8.0), 7.22 (td, 1H, J ¼ 7.7,
1.3), 7.16 (td, 1H, J ¼ 7.7, 1.3), 3.08 (m, 2H), 2.82 (m,
2H); 13C NMR (dimethyl sulfoxide-d6):
d 194.7, 167.7,
142.2, 129.8, 127.6, 122.9, 121.5, 119.4, 112.6, 40.6, 21.0;
ms: m/z 171 (Mþ). Anal. Calcd. for C11H9NO: C, 77.19; H,
5.26; N, 8.19. Found: C, 76.94; H, 5.20; N, 8.23.
151ꢀC (lit [25] mp 151–153ꢀC). IR: 1731 cm
;
1H NMR: d
1,2,3,9-Tetrahydro-4H-carbazol-4-one (7b). This com-
pound was prepared from 150 mg (0.74 mmoles) of 6b using a
modified procedure. In this case, 844 mg (4.44 mmoles, 6.0
eq) of p-toluenesulfonic acid monohydrate was required and
this was added in 2.0-eq portions at 1-h intervals during the
first 3 h of the 12-h reflux period. Product 7b (120 mg, 88%)
was isolated as an off-white solid, mp 225–228ꢀC (dec) (lit
8.07 (m, 1H), 7.48 (m, 1H), 7.25 (m, 2H), 6.27 (s, 1H), 3.14
(A of ABm, 2H), 3.08 (B of ABm, 2H); 13C NMR: d 171.6,
143.6, 135.3, 130.4, 124.0, 123.2, 120.5, 113.5, 100.3, 34.9,
19.6; ms: m/z 171 (Mþ). Anal. Calcd. for C11H9NO: C, 77.19;
H, 5.26; N, 8.19. Found: C, 77.14; H, 5.24; N, 8.21.
8,9-Dihydropyrido[1,2-a]indol-6(7H)-one (8b). This com-
pound was prepared by dissolving 100 mg (0.49 mmoles) of
6b in 15 mL of dry toluene and refluxing for 36 h. The reac-
tion mixture was cooled and the solvent was evaporated to
dryness under vacuum. The crude product was purified by
preparative thin layer chromatography using 50% ether in hex-
anes to give 82 mg (90%) of 8b as a white solid, mp 78–79ꢀC
[11] mp 219–221ꢀC). IR: 3368, 1588, 1566 cmꢂ1 1H NMR
;
(dimethyl sulfoxide-d6): d 11.7 (br s, 1H), 7.99 (d, 1H, J ¼
7.5), 7.46 (dd, 1H, J ¼ 7.8, 1.1), 7.25 (td, 1H, J ¼ 7.7, 1.2),
7.19 (td, 1H, J ¼ 7.7, 1.2), 2.99 (t, 2H, J ¼ 6.3), 2.42 (t, 2H,
J ¼ 6.4), 2.13 (quintet, 2H, J ¼ 6.4); 13C NMR (dimethyl sulf-
oxide-d6): d 192.1, 148.4, 134.1, 122.7, 122.2, 120.5, 120.2,
108.8, 106.5, 37.7, 22.9, 20.4; ms: m/z 185 (Mþ). Anal. Calcd.
for C12H11NO: C, 77.84; H, 5.95; N, 7.57. Found: C, 77.78;
H, 5.94; N, 7.60.
1
(lit [25] mp 79–81ꢀC). IR: 1690, cmꢂ1; H NMR: d 8.44 (dd,
1H, J ¼ 8.1, 0.9), 7.45 (dd, 1H, J ¼ 6.8, 1.6), 7.25 (m, 2H),
6.31 (s, 1H), 2.97 (td, 2H, J ¼ 6.8, 1.2), 2.78 (t, 2H, J ¼ 6.4),
2.07 (quintet, 2H, J ¼ 6.4); 13C NMR: d 169.4, 138.1, 134.8,
129.7, 124.0, 123.9, 119.6, 116.3, 104.8, 34.4, 23.8, 21.4; ms:
m/z 185 (Mþ). Anal. Calcd. for C12H11NO: C, 77.84; H, 5.95;
N, 7.57. Found: C, 77.76; H, 5.93; N, 7.59.
6,7,8,9-Tetrahydrocyclohept[b]indol-10(5H)-one (7c). This
compound was prepared as described for 7b using 203 mg
(0.93 mmoles) of 6c to give 133 mg (72%) of 7c as a tan
solid, mp 217–218 ꢀC (lit [11] mp 220–221ꢀC). IR: 3365,
1718 cmꢂ1 1H NMR (dimethyl sulfoxide-d6): d 11.7 (br s,
;
7,8,9,10-Tetrahydro-6H-azepino[1,2-a]indol-6-one (8c). This
compound was prepared as described for 8a on an 80 mg
(0.37 mmole) scale to give 60 mg (81%) of the lactam as a
1H), 8.14 (dd, 1H, J ¼ 7.4, 1.4), 7.34 (dd, 1H, J ¼ 7.9, 1.3),
7.12 (m, 2H), 3.10 (t, 2H, J ¼ 6.3), 2.64 (m, 2H), 1.93 (quin-
tet, 2H, J ¼ 6.4), 1.83 (m, 2H); 13C NMR (dimethyl sulfoxide-
d6): d 196.4, 149.0, 135.0, 127.3, 122.2, 121.2, 120.9, 113.7,
110.9, 42.7, 27.0, 24.3, 21.8; ms: m/z 199 (Mþ). Anal. Calcd.
for C13H13NO: C, 78.39; H, 6.53; N, 7.04. Found: C, 78.19;
H, 6.48; N, 7.05.
1
white solid, mp 172–175ꢀC. IR: 1692 cmꢂ1; H NMR: d 8.42
(dm, 1H, J ¼ 7.9), 7.46 (dm, 1H, J ¼ 7.3), 7.32–7.20 (com-
plex, 2H), 6.36 (s, 1H), 3.06 (t, 2H, J ¼ 5.9), 2.94 (distorted t,
2H, J ¼ 5.8), 1.94 (m, 4H); 13C NMR: d 173.8, 139.5, 136.9,
129.6, 124.1, 123.5, 119.5, 116.3, 107.9, 35.9, 25.8, 23.7, 20.8;
ms: m/z 199 (Mþ). Anal. Calcd. for C13H13NO: C, 78.39; H,
6.53; N, 7.04. Found: C, 78.35; H, 6.54; N, 7.06.
Direct preparation of 7b from 4b. A 100-mL single-
necked round-bottomed flask equipped with a reflux condenser
(N2 inlet) and a magnetic stir bar was charged with 200 mg
(0.75 mmoles) of 4b and 8 mL of concentrated hydrochloric
acid. The mixture was heated to 80ꢀC (oil bath) and 126 mg
(2.25 mmoles, 3.0 eq) of iron powder (>100 mesh) was added
(Caution! This addition is sufficiently exothermic to boil the
mixture). The reaction is contained by using a large flask and
immediately replacing the condenser after adding the iron). The
reaction was refluxed at 110ꢀC until thin layer chromatography
indicated complete consumption of starting material (ca 20
min), then cooled, added to 15 mL of water and extracted with
ether (three times). The combined ether layers were washed with
saturated sodium chloride (one time), dried (magnesium sulfate)
and concentrated under vacuum. The resulting solid was flash
chromatographed on a 20 cm ꢃ 2 cm silica gel column eluted
with increasing concentrations of ether in hexanes to give 128
mg (92%) of 7b. The physical properties and spectral data
matched those reported above.
Acknowledgment. B. N. thanks the Department of Chemistry at
Oklahoma State University for a teaching assistantship. Funding
for the 300 MHz NMR spectrometer of the Oklahoma Statewide
Shared NMR Facility was provided by NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W. M. Keck
Foundation, and Conoco, Inc. Finally, the authors wish to thank
the OSU College of Arts and Sciences for funds to upgrade our
departmental FTIR and GC-MS instruments.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet