Synthesis of substituted indoles and carbazoles from 2-fluorophenyl imines

Article abstract of DOI:10.1055/s-2003-40880

The synthesis of a series of indole and carbazole derivatives from 2-fluorophenyl imines is reported. 2-Fluoroaniline-d₄ (13) is prepared and used to investigate the mechanism of this indolization. 2-Fluorophenyl enaminone 17 gives the synthetically useful carbazole 20 via a similar indolization and in situ alkylation.

Full text of DOI:10.1055/s-2003-40880

PAPER
1661
Synthesis of Substituted Indoles and Carbazoles from 2-Fluorophenyl Imines
S
ynthesis of Su
i
bstitute
n
d
Indoles
a
n
a
d Carbazole
s
s
from 2-Fluoro
V
phenyl Imines . Kudzma*
Baxter Healthcare Corporation, Anesthesia and Critical Care, 95 Spring Street, New Providence, NJ 07974, USA
Fax +1(908)2867359; E-mail: linas_kudzma@baxter.com
Received 9 May 2003
toluene by acid-catalyzed azeotropic dehydration. The re-
Abstract: The synthesis of a series of indole and carbazole deriva-
tives from 2-fluorophenyl imines is reported. 2-Fluoroaniline-d4
(13) is prepared and used to investigate the mechanism of this in-
dolization. 2-Fluorophenyl enaminone 17 gives the synthetically
sulting 2-fluorophenyl imines can be purified by chroma-
tography or distillation and fully characterized5 if so
desired. Alternatively, the majority of toluene can be dis-
useful carbazole 20 via a similar indolization and in situ alkylation. tilled off in vacuo and the resultant crude imine used di-
rectly, as demonstrated in the high yielding synthesis of
carbazole 6. The reaction of acetophenone and 2-fluoro-
aniline produced an interesting unexpected side product.
In this case, attempts to drive the azeotropic dehydration
to completion gave varying amounts of 2,4-diphenyl-3H-
1-benzazepine (9),6 presumably from an aldol-type con-
densation followed by an intramolecular SNAr ring clo-
sure under unprecedented conditions (Figure 1).
Similarly, 2-acetylthiophene and 2-fluoroaniline under
acid-catalyzed azeotropic dehydration can give the analo-
gous dithienyl-3H-1-benzazepine (10).
Key words: indoles, imines, enaminone, benzyne, nucleophilic ar-
omatic substitution
Synthesis of selectively functionalized indole and carba-
zole derivatives continues to attract interest in organic
synthesis1 due to the extensive presence of indoles in nat-
ural products and biologically active compounds in me-
dicinal chemistry.2 The method described in this article
provides a new short route to 2- or 2,3-disubstituted in-
doles from appropriately substituted 2-fluorophenyl imi-
nes and a 2-fluorophenyl enaminone. This method
complements a related route to indole derivatives from 3-
chlorophenyl imines and enamines.3
R
N
a, b
Bn
N
N
Bn
N
9
R = Ph
NH
R
10 R =
F
S
1
2 (97%)
Figure 1
Scheme 1 Reagents and conditions: a) 2.5 equiv LDA, THF, reflux
5 h; b) H2O
The mechanism and synthetic utility of this benzazepine
synthesis are presently being investigated and full details
will be reported separately. Despite this side reaction, it is
possible to obtain the desired imines 4 and 5 in modest
yield if the reaction is not driven to completion and the
imines are isolated by chromatography.
During a large scale synthesis of a 4-anilidopiperidine
opioid analgesic4 involving the addition of phenyllithium
to imine 1, a previously overlooked minor side product
was isolated and determined to be the gamma-carboline
derivative 2. Reaction conditions were modified to make
this initially unexpected indole derivative the exclusive
product (Scheme 1). Treatment of imine 1 with a mini-
mum of two equivalents of the non-nucleophilic base
LDA and heating the reaction mixture to reflux, cleanly
gave the indole derivative 2 in nearly quantitative yield.
Additional investigation found that this is a general meth-
od for preparing 2- or 2,3-disubstituted indoles in good to
excellent yields from appropriately substituted 2-fluoro-
phenyl imines (Table 1).
To synthesize indole derivatives from 2-fluorophenyl
imines, the imines were dissolved in anhydrous THF un-
der an atmosphere of dry nitrogen, cooled to –78 °C and
treated with 2.5–3 equivalents of LDA followed by heat-
ing to reflux. The reactions were monitored by TLC anal-
ysis and showed only a small amount of indolization as
the reaction mixture warmed to ambient temperature.
Typically, several hours at reflux under nitrogen were
needed to complete the displacement of the aromatic flu-
orine. The need for a minimum of 2 equivalents of LDA
strongly suggested that this aromatic substitution involves
a benzyne rather than a SNAr mechanism. The intermedi-
acy of a benzyne was demonstrated by the use of 2-fluo-
roaniline-d4 in the synthesis.
2-Fluorophenyl imines were easily obtained from 2-
fluoroaniline and the corresponding ketone in refluxing
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1661,1666,ftx,en;C03103SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
2-Fluoroaniline-d4 (13) was prepared (Scheme 2), from
fluorobenzene-d5,7 which was ortho lithiated using Schlo-
sser’s ‘super base’ protocol8 and quenched with solid car-

1662
L. V. Kudzma
PAPER
Table 1 Indolization of Imines 1, 3–5
Imine
Indole
Yield (%)
97
Conditions
1
2
6
LDA (2.5 equiv)
reflux 5 h
Bz
N
N
Bn
N
NH
F
3
93
LDA (2.5 equiv)
reflux 5 h
HN
F
N
4
5
7
8
90
42
LDA (3 equiv)
reflux 5 h
HN
F
Ph
N
Ph
CH3
LDA (2.5 equiv)
reflux 16 h
HN
F
N
S
CH3
S
F
F
of deuterium label at this location could be easily ob-
served. The spectrum of indole 16 only showed exchange
of deuterium at 7.59 (C-4), which is adjacent to the
former location of the aromatic fluorine. This strongly in-
dicates that lithiation occurs at this site, followed by elim-
ination of fluoride to form the proposed benzyne
intermediate 15.
CO2H
a, b
d5
d4
11 (89%)
c, d
F
A further extension of this new indolization method was
F
NH2
used to synthesize the important carbazole derivative 20
CONH2
e
d4
d4
13 (53%)
12 (74%)
d4
Scheme 2 Reagents and conditions: a) n-BuLi/t-BuOK, THF –78
°C, 1 h; b) CO2 (s); c) SOCl2, reflux 1.5 h; d) NH3, CH2Cl2, 0 to 20
°C; e) aq NaOH, Br2, reflux 1.5 h, steam distill.
F
N
O
a
CH3
CH3
S
S
14
bon dioxide to give 2-fluorobenzoic acid-d4 (11) in
excellent yield. This acid was then converted to 2-fluoro-
benzamide-d4 (12) by heating with neat thionyl chloride
followed by treatment of the crude acid chloride with am-
monia in dichloromethane. The amide 12 was converted
to 2-fluoroaniline-d4 (13) under standard Hofmann rear-
rangement conditions without loss of deuterium label.
b
d3
d3
c
HN
4
NLi
H
2-Fluoroaniline-d4 (13) was reacted with 2-acetylth-
iophene to give the imine 14 and indolization under the
typical conditions (Scheme 3) gave the deuterium labeled
indole 16. This deuterated indole 16 was chosen for the la-
S
CH2
S
16
15
1
Scheme 3 Reagents and conditions: a) 13, toluene, p-TsOH, reflux,
separate H2O, 4 h; b) 2.5 equiv LDA, THF, reflux 16 h; c) H2O
beled experiment because the H NMR resonance at C-4
was cleanly resolved from other Ar-H resonances and loss
Synthesis 2003, No. 11, 1661–1666 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Indoles and Carbazoles from 2-Fluorophenyl Imines
1663
from the 2-fluorophenyl enaminone 17 (Scheme 4). The In conclusion, the indolization method described in this
enaminone 17 was prepared from 1,3-cyclohexanedione paper is generally applicable for the synthesis of a variety
and 2-fluoroaniline by heating them neat at 120 °C in a of 2- or 2,3-disubstituted indoles and provides a new effi-
manner analogous to that described by Kibayashi9 and cient route to diverse indole derivatives.
treated with 3 equivalents of LDA in THF. In contrast to
the previous cases, 17 required a minimum of 3 equiva-
Reagents and solvents were used as received from commercial ven-
lents of LDA for indolization to occur. If only 2 equiva-
lents were used, even prolonged heating at 75 °C did not
result in any indolization. With 3 equivalents of LDA, in-
dolization proceeded in the normal manner giving the de-
sired carbazole dianion 18. The dianion 18 was partially
quenched with one equivalent of acetic acid, followed by
in situ alkylation with methyl iodide to give the desired N-
methyl carbazole 20. This one-pot lithiation, indolization,
partial quench, alkylation protocol was found to be a very
convenient route to 20, a pivotal intermediate in the syn-
thesis of the antiemetic drug ondansetron10 and related
compounds.
dors without further purification. Anhyd THF, 1.8 M LDA in hep-
tane/THF/ethylbenzene, 1.5 lithium diisopropylamide
M
mono(tetrahydrofuran) in cyclohexane and 2.5 M n-butyllithium in
hexanes were obtained in Sure/Seal™ bottles from Aldrich Chemi-
cal Co., Milwaukee, WI and transferred via syringe under dry nitro-
gen. Melting points were determined on a Melt-Temp II capillary
melting-point apparatus and are uncorrected. Mass spectra were ob-
tained on a Waters GCT TOF mass spectrometer. 1H, 13C, and 19F
NMR spectra were obtained on Bruker BioSpin Avance 300 (1H
300 MHz, 13C 75 MHz, 19F 282 MHz) or JEOL GSX-270 (1H 270
MHz) Nuclear Resonance Spectrometers and data are reported with
in ppm and J in Hz. TLC analyses were performed using J.T. Bak-
er IB-F silica gel plates with fluorescent indicator and visualized
with UV light. Flash chromatography was on Silica 60 (230–400
mesh) from EM Science. Elemental analyses were performed by
Robertson Microlit Laboratories, Inc., Madison NJ.
Alternatively, the reaction mixture containing dianion 18
can be quenched with excess acetic acid, protected from
exposure to air, and quickly purified by flash chromato-
graphy to give the carbazole 21.11 It is noteworthy that
when this reaction was quenched with excess water, the
alkaline crude reaction mixture containing 21 was very
sensitive to oxidative decomposition. If an N-alkyl carba-
zole is the ultimate goal, it is best to perform the alkylation
in situ as described for 20.
N-(1-Benzylpiperidin-4-ylidene)-N-(2-fluorophenyl)amine (1)
N-Benzyl-4-piperidone (5.55 g, 29.3 mmol), 2-fluoroaniline (2.85
g, 25.7 mmol) and catalytic p-TsOH (65 mg) were combined in tol-
uene (100 mL) and heated at reflux with removal of H2O using a
Dean–Stark trap. After 15 h the reaction was cooled to r.t. and con-
centrated in vacuo. The crude reaction mixture was then vacuum
distilled bulb-to-bulb, using a Buchi Kugelrhor apparatus (250 °C,
2 mmHg), to give 1 as a bright yellow oil which solidified upon
standing; yield: 6.68 g (92%). This material was sufficiently pure to
be used without further purification. An analytical sample was crys-
tallized from hexane; mp 70–72 °C; Rf 0.40 (EtOAc–hexanes, 1:2).
1H NMR (CDCl3): = 7.34–7.25 (complex m, 5 H), 7.03 (m, 3 H),
6.82 (m, 1 H), 3.58 (s, 2 H), 2.72 (m, 2 H), 2.66 (m, 2 H), 2.55 (t,
J = 5.8 Hz, 2 H), 2.29 (t, J = 5.8 Hz, 2 H).
13C NMR (CDCl3): = 175.33, 153.86, 150.63, 138.35, 137.93,
137.75, 129.31, 128.33, 127.21, 124.51, 124.42, 124.28, 124.23,
122.82, 122.79, 115.95, 115.68, 62.24, 53.94, 53.25, 38.35, 31.82.
F
O
NH
a
O
O
17
b
Anal. Calcd for C18H19FN2 (282.36): C, 76.57; H, 6.78; N, 9.92.
Found: C, 76.59, H, 6.91; N, 9.79.
(2-Fluorophenyl)-N-(1-phenylethylidene)amine (4)
LiN
LiN
c
Acetophenone (6.0 g, 50 mmol), 2-fluoroaniline (5.6 g, 50 mmol)
and p-TsOH (cat., 25 mg) were combined in toluene (150 mL) and
heated at reflux with removal of H2O using a Dean–Stark trap. After
4 h12 the reaction was cooled to r.t. and washed with 5% aq Na2CO3
(50 mL). The organic layer was separated, dried over anhyd Na2SO4
and filtered. Silica gel (15 g) was added and the toluene solution
was evaporated to adsorb the product onto silica, which was then
applied to a silica column and purified by flash chromatography,
(EtOAc–hexanes, 1:10) to give 4 as an orange oil; yield: 4.66 g
(44%); Rf 0.56 (EtOAc–hexanes, 1:10).
OLi
O
19
18
d
e
Me
1H NMR (CDCl3): = 7.99 (complex m, 2 H), 7.42 (complex m, 3
H), 7.12–7.05 (complex m, 3 H), 6.89 (m, 1 H), 2.23, 2.22 (2 s, total
3 H).
N
HN
13C NMR (CDCl3): = 168.35, 153.67, 150.44, 139.29, 139.11,
130.89, 128.49, 127.52, 124.61, 124.54, 124.52, 124.49, 122.42,
122.39, 116.19, 115.92, 17.95, 17.92.
O
O
20 (27%)
21 (33%)
HRMS: m/z calcd for C14H12FN, 213.0954; found, 213.0974.
Scheme 4 Reagents and conditions: a) 2-fluoroaniline, 120 °C, 3 h;
b) 3 equiv LDA, THF, 75 °C, 2.5 h; c) 1 equiv HOAc; d) MeI; e) 7
equiv HOAc.
Synthesis 2003, No. 11, 1661–1666 © Thieme Stuttgart · New York

1664
L. V. Kudzma
PAPER
(2-Fluorophenyl)-N-(1-thien-2-ylethylidene)amine (5)
2-Acetylthiophene (2.51 g, 19.9 mmol), 2-fluoroaniline (2.22 g,
20.0 mmol) and p-TsOH (cat., 25 mg) were combined in toluene (50
mL) and heated at reflux with removal of H2O using a Dean–Stark
trap. After 4 h12 the reaction was cooled to r.t., diluted with of tolu-
ene (50 mL) and washed with 5% aq Na2CO3 (25 mL). The organic
layer was separated, dried over anhyd Na2SO4, and filtered. Silica
gel (10 g) was added and the toluene solution evaporated to adsorb
the product on to the silica, which was then applied to a silica col-
umn and purified by flash chromatography (EtOAc–hexanes, 1:20)
to give 5 as a yellow glass, which solidified to a waxy solid upon
refrigeration; yield: 2.28 g (52%); mp 51 °C; Rf 0.50 (EtOAc–hex-
anes, 1:20).
1H NMR (CDCl3): = 7.47–7.43 (m, 2 H), 7.09–7.03 (complex m,
4 H), 6.90 (m, 1 H), 2.20,2.21 (2 s, total 3 H).
13C NMR (CDCl3): = 163.07, 153.93, 150.69, 145.87, 138.08,
137.91, 130.51, 129.10, 127.57, 124.84, 124.74, 124.37, 124.32,
122.90, 122.86, 116.08, 115.81, 18.04, 18.01. Anal. Calcd for
C12H10FNS (219.28): C, 65.73; H, 4.60; N, 6.39. Found: C, 65.64,
H, 4.56; N, 6.23.
mp 164 °C (lit.14 164–165 °C); Rf 0.48 (EtOAc–hexanes, 1:10),
blue-fluorescent spot.
1H NMR (CDCl3): = 8.18 (br s, 1 H), 7.56 (d, J = 7.6 Hz, 1 H),
7.39–7.10 (complex m, 7 H), 3.07 (m, 2 H), 2.97 (m, 2 H).
13C NMR (CDCl3): = 137.07, 136.59, 133.10, 128.93, 128.54,
127.53, 126.77, 126.67, 122.40, 119.95, 119.87, 118.84, 112.74,
111.20, 29.58, 19.74.
2-Phenyl-1H-indole (7)
The imine 4 (1.16 g, 5.44 mmol) was dissolved in anhyd THF
(30mL) under N2 in an oven dried flask equipped with a reflux con-
denser. The solution was cooled to –78 °C and LDA THF (1.5 M,
11 mL, 16.5 mmol) in cyclohexane was added via syringe. The re-
action was stirred at –78 °C for 15 min, then warmed to r.t. and heat-
ed to reflux under an atmosphere of N2. After 5 h at reflux the
reaction was cooled to r.t., quenched with H2O (3 mL) and concen-
trated in vacuo. The residue was partitioned between H2O (50 mL)
and CH2Cl2 (100 mL). The organic layer was separated, dried over
anhyd Na2SO4, and evaporated in vacuo. The residue was purified
by flash chromatography (EtOAc–hexanes, 1:10) to give 7 as a tan
solid; yield: 0.95 g (90%). An analytical sample was crystallized
from EtOAc–hexane; mp 190 °C (lit.15 186–188 °C); Rf 0.25
(EtOAc–hexanes, 1:10), blue-fluorescent spot.
2-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2)
The imine 1 (1.03 g, 3.65 mmol) was dissolved in anhyd THF (30
mL) under N2 in an oven dried flask equipped with a reflux con-
denser. The solution was cooled to –78 °C and LDA·THF (1.5 M, 6
mL, 9.0 mmol) in cyclohexane was added via syringe. The reaction
was stirred at –78 °C for 15 min, then warmed to r.t. and heated to
reflux under an atmosphere of N2. TLC analysis showed a quantita-
tive conversion to a new product after 5 h at reflux and the reaction
was cooled to r.t., quenched with H2O (10 mL) and partitioned be-
tween additional H2O (100 mL) and CH2Cl2 (150 mL). The organic
layer was separated, dried over anhyd Na2SO4 and evaporated in
vacuo. The residue was purified by flash chromatography (EtOAc–
hexanes, 1:1) to give 2 as a yellow solid; yield: 0.92 g (97%). An
analytical sample was crystallized from EtOAc–hexane; mp 160–
161 °C; Rf 0.40 (EtOAc–hexanes, 1:1).
1H NMR (CDCl3): = 7.80 (br s, 1 H), 7.44–7.25 (complex m, 7 H),
7.07 (m, 2 H), 3.80 (s, 2 H), 3.73 (br s, 2 H), 2.87 (m, 4 H).
13C NMR (CDCl3): = 138.71, 136.09, 132.19, 129.16, 128.36,
127.15, 126.21, 121.13, 119.26, 117.56, 110.61, 108.80, 62.40,
50.14, 49.81, 23.73.
13C NMR (CDCl3): = 137.57, 137.08, 132.18, 128.83, 128.58,
127.33, 124.94, 121.49, 119.97, 119.30, 111.24, 98.61.
2-Thien-2-yl-1H-indole (8)
The imine 5 (0.67 g, 3.0 mmol) was dissolved in anhyd THF
(30mL) under N2 in an oven dried flask equipped with a reflux con-
denser. The solution was cooled to –78 °C and LDA (1.8 M, 4 mL,
7.2 mmol) in heptane–THF–ethylbenzene was added via syringe.
The reaction was stirred at –78 °C for 15 min, then warmed to r.t.
and heated to reflux under an atmosphere of N2. After 16 h at reflux
the reaction was cooled to r.t., quenched with H2O (10 mL) and con-
centrated in vacuo. The residue was partitioned between H2O (50
mL) and CH2Cl2 (100 mL). The organic layer was separated, dried
over anhyd MgSO4 and evaporated in vacuo. The residue was puri-
fied by flash chromatography (hexanes–CH2Cl2, 1:1) to give 8 as a
tan solid; yield 253 mg (42%). An analytical sample was crystal-
lized from EtOAc–hexane; mp 167–168 °C; Rf 0.40 (hexanes–
CH2Cl2, 1:1).
1H NMR (CDCl3): = 8.20 (br s, 1 H), 7.59 (d, J = 7.8 Hz, 1 H),
7.37 (d, J = 7.8 Hz, 1 H), 7.29–7.08 (complex m, 5 H), 6.74 (dd,
J = 0.85, 2.1 Hz, 1 H).
Anal. Calcd for C18H18N2 (262.35): C, 82.41; H, 6.92; N, 10.68.
Found: C, 82.32; H, 6.73; N, 10.64.
5,6-Dihydro-11H-benzo[a]carbazole (6)
13C NMR (CDCl3): = 135.50, 134.60, 131.31, 128.08, 126.85,
123.55, 121.89, 121.52, 119.52, 119.43, 109.74, 99.43.
-Tetralone (3.30 g, 22.6 mmol), 2-fluoroaniline (2.51 g, 22.6
mmol) and p-TsOH (cat., 25 mg) were combined in toluene (100
mL) and heated at reflux with removal of H2O using a Dean–Stark
trap. After 15 h the reaction was cooled to r.t., and the toluene evap-
orated in vacuo to give N-3,4-dihydronaphthalen-1(2H)-ylidene-N-
(2-fluorophenyl)amine (3) as a dark oil. The crude imine was suffi-
ciently pure to be used without further purification13 and was dis-
solved in anhyd THF (25 mL) under N2 and the flask was equipped
with a reflux condenser. The solution was cooled to –78 °C and
LDA·THF (1.5 M, 37 mL, 55.5 mmol) in cyclohexane was added
via syringe. The reaction was stirred at –78 °C for 15 min, then
warmed to r.t. and heated to reflux under an atmosphere of N2. TLC
analysis showed a quantitative conversion to a new product after 5
h at reflux and the reaction was cooled to r.t., quenched with H2O
(10 mL) and concentrated in vacuo. The residue was partitioned be-
tween H2O (100 mL) and CH2Cl2 (150 mL) and the organic layer
was separated, dried over anhyd MgSO4 and evaporated in vacuo.
The residue was purified by flash chromatography (EtOAc–hex-
anes, 1:10) to give 6 as a tan solid; yield 4.59 g (93%). An analytical
sample was crystallized from EtOAc–hexane to give tan crystals;
Anal. Calcd for C12H9NS (199.27): C, 72.33; H, 4.55; N, 7.03.
Found: C, 72.16; H, 4.37; N, 6.94.
2-Fluorobenzoic Acid-d4 (11)
t-BuOK in THF (1.0 M, 25 mL, 25 mmol) was added to THF (40
mL) under N2, cooled to –78 °C, and n-BuLi in hexanes (2.5 M, 10
mL, 25 mmol) was added. After stirring at –78 °C for 0.5 h, fluoro-
benzene-d5 (2.40 g, 23.73 mmol) was added dropwise via syringe
over 5 min. The reaction was stirred at –78 °C for 1.5 h, then a large
excess of crushed solid CO2 (7 g) was added in one portion rapidly
discharging the deep red color of the reaction mixture. The reaction
was allowed to warm to r.t. and H2O (20 mL) was added and the re-
action mixture was concentrated in vacuo to remove the majority of
THF. The residue was partitioned between 10% aq NaOH (50 mL)
and Et2O (100 mL). The water layer was separated and acidified
with 6 N aq HCl and a solid precipitated. This slurry was extracted
with Et2O (100 mL) and the Et2O layer was dried over anhydrous
Na2SO4 and concentrated in vacuo to give the acid 11 as a white sol-
id; yield: 3.05 g (89%); mp 123–124 °C
Synthesis 2003, No. 11, 1661–1666 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Indoles and Carbazoles from 2-Fluorophenyl Imines
1665
19F NMR (CDCl3): = –108.4.
1,2,3,9-Tetrahydro-9-methyl-4H-carbazole-4-one (20)
The enaminone 17 (3.25 g, 15.8 mmol) was dissolved in anhyd THF
(100 mL) under N2 in an oven-dried flask equipped with a reflux
condenser. The solution was cooled to 0 °C and LDA·THF (1.5 M,
32 mL, 48 mmol) in cyclohexane was added via syringe. The reac-
tion was stirred at 0 °C for 15 min and then heated to 75 °C in a tem-
perature controlled oil bath. After 2.5 h at 75 °C the reaction was
cooled to r.t., glacial HOAc (1.0 g, 16.6 mmol) was added and the
mixture was stirred at r.t for 0.5 h before addition of MeI (2.26 g,
15.9 mmol) in one portion. After 6 h at r.t. the reaction mixture was
evaporated in vacuo and the residue was partitioned between H2O
(150 mL) and CH2Cl2 (200 mL). The organic layer was separated,
dried over anhyd Na2SO4, and evaporated in vacuo. The residue was
purified by flash chromatography (EtOAc–hexanes, 2:1) to give 20
as a tan solid; yield: (27%). An analytical sample was crystallized
from EtOAc–hexane; mp 195–196 °C; Rf 0.32 (EtOAc–hexanes,
2:1).
Anal. Calcd for C7D4HFO (144.14): C, 58.33. Found: C, 58.46.
2-Fluorobenzamide-d4 (12)
The acid 11 (3.05 g, 21.16 mmol) was treated with neat excess
SOCl2 (16 g, 134 mmol) at reflux for 1.5 h and the SOCl2 evaporat-
ed in vacuo to give a greenish-brown oil. This oil was dissolved in
CH2Cl2 (50 mL) and the solution cooled in an ice bath while liquid
NH3 (20 mL) was added to the stirring solution by condensation
from an acetone/solid CO2 cold finger condenser. The reaction was
left to warm to r.t. overnight to evaporate excess NH3. The residue
was evaporated to dryness in vacuo and the solid residue was parti-
tioned between H2O (50 mL) and CH2Cl2 (100 mL). The organic
layer was separated, dried over anhydrous Na2SO4 and evaporated
in vacuo to give the amide 12 as a white solid; yield: 2.24 g (74%);
mp 116–118 °C.
1H NMR (CDCl3): = 6.70 (br s), 6.26 (br s).
19F NMR (CDCl3): = –113.0.
1H NMR (CDCl3): = 8.25 (m, 1 H), 7.27 (m, 3 H), 3.69 (s, 3 H),
2.91 (t, J = 6.2 Hz, 2 H), 2.56 (t, J = 6.4 Hz, 2 H), 2.24 (m, 2 H).
13C NMR (CDCl3): = 193.64, 151.75, 137.38, 124.76, 122.91,
122.51, 121.62, 122.66, 109.04, 37.84, 29.79, 23.28, 22.14.
Anal. Calcd for C7D4H2FNO (143.15): C, 58.73; N, 9.78. Found: C,
58.36; H, 9.53.
Anal. Calcd for C13H13NO (199.25): C, 78.36; H, 6.58; N, 7.03.
Found: C, 78.16; H, 6.27; N, 6.87.
2-Fluoroaniline-d4 (13)
Br2 (3.71 g, 23.21 mmol) was added to a cold (0 °C) solution of
NaOH (3.09 g, 77.25 mmol) in H2O (50 mL) and stirred until homo-
geneous. The solid amide 12 (2.20 g, 15.37 mmol) was added and
the mixture was heated at reflux for 1.5 h. Distillation of approxi-
mately half of the reaction volume gave the desired product as a sep-
arate layer in the distillate, which was extracted with CH2Cl2 (25
mL). The organic layer was separated and concentrated in vacuo
leaving the desired aniline 13 as an orange liquid; yield: 0.94 g
(53%).
Acknowledgment
The author thanks Dr. Eun Jang (Baxter) for mass spectra and Dr.
Ralph Lessor (Baxter) and Dr. Keith Ramig (Baruch College) for
useful discussions and encouragement.
References
1H NMR (CDCl3): = 3.70 (br s).
19F NMR (CDCl3): = –135.8.
(1) For a review of indolization methods see: Pindur, U.; Adam,
R. J. Heterocycl. Chem. 1988, 1.
HRMS: m/z calcd for C6D4H2FN,115.0735; found, 115.0743.
(2) Sunberg, R. J. Indoles; Academic Press: London, 1996.
(3) Caubere, C.; Caubere, P.; Renard, P.; Bizot-Espiart, J.-G.;
Jamart-Gregoire, B. Tetrahedon Lett. 1993, 6889.
(4) Kudzma, L. V.; Severnak, S. A.; Benvenga, M. J.; Ezell, E.
F.; Ossipov, M. H.; Knight, V. V.; Rudo, F. G.; Spencer, H.
K.; Spaulding, T. C. J. Med. Chem. 1989, 2534.
(5) Certain 1H- and 13C NMR resonances of imines are finely
doubled due to closely overlapping spectra of syn- and anti-
isomers: Bunnell, C. A.; Fuchs, P. L. J. Org. Chem. 1977,
2614.
2-Thien-2-yl-1H-indole-d3 (16)
The title compound was prepared from 2-acetylthiophene and 2-flu-
oroaniline-d4 (13) by the procedure described for indole 8 to give 16
as a tan solid.
1H NMR (CDCl3): = 8.21 (br s, 1 H), 7.59 (s, 1 H, C-4), 7.30–7.26
(m, 2 H), 7.09 (m, 1 H), 6.73 (d, J = 2.2 Hz, 1 H).
3-[(2-Fluorophenyl)amino]cyclohex-2-en-1-one (17)
(6) 2,4-Diphenyl-3H-1-benzazepine(9), mp 129–30 °C. 1H
NMR (CDCl3): = 7.86 (m 2 H), 7.60–7.31 (complex m, 11
H), 7.21 (m, 1 H), 7.07 (s, 1 H), 3.38 (s, 2 H). 13C NMR
(CDCl3): = 157.33, 146.89, 139.93, 138.24, 134.94,
130.55, 130.15, 129.56, 128.78, 128.53, 128.04, 127.99,
127.90, 126.97, 126.86, 126.82, 123.98, 33.90. Anal. Calcd
for C22H17N (295.38): C, 89.46; H, 5.80; N, 4.74. Found: C,
89.24 H, 5.68 N, 4.68.
(7) Fluorobenzene-d5, 97 atom%D was obtained from Aldrich
Chemical Co., Milwaukee WI USA.
(8) Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett 1990,
747.
(9) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1979, 1074.
(10) U.S. Adopted Name for: 1,2,3,9-tetrahydro-9-methyl-3-[(2-
methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one:
Coates, I. H.; Bell, J. A.; Humber, D. C.; Ewan, G. B. Eur.
Pat. Appl. EP 191562, 1986.
(11) 1,2,3,9-Tetrahydro-4H-carbazole-4-one(21) can be isolated
as a tan solid; mp 219–221 °C; Rf 045 (EtOAc–hexanes,
2:1). 1H NMR (DMSO-d6): = 11.85 (br s, 1 H), 7.96 (m, 1
H), 7.40 (m, 1 H), 7.15 (m, 2 H), 2.96 (t, J = 6.2 Hz, 2 H),
1,3-Cyclohexanedione (22.43 g, 200 mmol) and 2-fluoroaniline
(22.30 g, 201 mmol) were combined neat and heated in a 120 °C oil
bath under N2 for 3 h. The reaction mixture was cooled to r.t. and
the resulting dark red glass was dissolved in CH2Cl2 (100 mL) and
applied to a short column of silica gel (50 gm) to retain polar impu-
rities. The product was eluted from the silica with EtOAc (1 L),
which was concentrated in vacuo to a volume of approximately 300
mL, from which the product crystallized upon refrigeration. The or-
ange crystals were filtered, washed with EtOAc–hexane (1:1, 50
mL), and dried in vacuo to give 25.51 g (62%) of enaminone 17; mp
136–137 °C; Rf 0.20 (EtOAc).
1H NMR (CDCl3): = 7.35–7.27 (m, 1 H), 7.15–7.07 (m, 3 H), 6.39
(br s, 1 H), 5.50 (s, 1 H), 2.54 (t, J = 6.5 Hz, 2 H), 2.36 (t, J = 6.5
Hz, 2 H), 2.04 (m, 2 H).
13C NMR (CDCl3): = 198.50, 163.58, 157.80, 154.51, 127.06,
126.96, 126.75, 126.17, 126.01, 124.38, 124.33, 116.36, 116.10,
99.63, 36.37, 29.07, 21.77.
Anal. Calcd for C12H12FNO (205.23): C, 70.23; H, 5.89; N, 6.82.
Found; C, 70.11; H, 5.81; N, 6.73.
Synthesis 2003, No. 11, 1661–1666 © Thieme Stuttgart · New York

1666
L. V. Kudzma
PAPER
2.43 (t, J = 6.2 Hz, 2 H), 2.12 (m, 2 H). 13C NMR (DMSO-
d6): = 192.78, 152.17, 135.80, 124.49, 122.35, 121.43,
120.14, 111.72, 111.45, 37.77, 23.38, 22.68.
(13) If desired the crude imine 3 can be distilled under reduced
pressure to give a colorless oil; bp 170–172 °C (0.25
mmHg).
(12) Longer reflux gives increasing amounts of the benzazepine
side product discussed in the text.
(14) Katritzky, A. R.; Wang, Z. J. Heterocycl. Chem. 1988, 671.
(15) Junjappa, H. Synthesis 1975, 798.
Synthesis 2003, No. 11, 1661–1666 © Thieme Stuttgart · New York