Syntheses of β,β-difluorotryptamines

Article abstract of DOI:10.1021/jo020731c

Tryptamines disubstituted at the β-position with fluorine have been synthesized as part of our research program to study the effects of fluorine substitution on the biological activities of neuroactive amines. Treatment of N-Boc-3-azidoacetyl indoles, pre

Full text of DOI:10.1021/jo020731c

Syn th eses of â,â-Diflu or otr yp ta m in es
Wei-Ping Deng,† Ghilsoo Nam,† J unfa Fan, and Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases,
National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892
kennethk@bdg8.niddk.nih.gov
Received December 9, 2002
Tryptamines disubstituted at the â-position with fluorine have been synthesized as part of our
research program to study the effects of fluorine substitution on the biological activities of
neuroactive amines. Treatment of N-Boc-3-azidoacetyl indoles, prepared from readily available
2-chloracetylindoles, with dimethoxyethylamino sulfurtrifluoride produced the corresponding 3-(2-
azido-1,1-difluoroethyl)indoles. Reduction of the azide to amine with hydrogen over Pd-C and careful
removal of the N-Boc protecting group produced â,â-difluorotryptamines.
In tr od u ction
ovnikoff addition of “FBr” to vinyl imidazoles as the key
step.3 Extending this effort to the indolic amines seemed
appropriate in view of the biological importance of
tryptamines.4 Side-chain fluorinated analogues of 5-hy-
droxytryptamine (serotonin, 1), an important neurotrans-
mitter, and of N-acetyl-5-methoxytryptamine (melatonin,
2), the key modulator of circadian rhythm, were particu-
Over the past several years we have prepared a series
of ring-fluorinated biogenic amines and amino acids,
including fluorinated analogues of catecholamines and
catecholamino acids (DOPAs), histamines and histidines,
and tryptamines.1 This series of compounds provided
many useful tools for biological and pharmacological
studies. During the course of this work, we had made
attempts to prepare side-chain analogues of certain of
these important amines and amino acids. The potential
value of such compounds has been demonstrated. In the
1970s, Fuller reported the synthesis and biological evalu-
ation of a series of side-chain fluorinated psychotomimetic
amines, including, for example, â,â-difluoroamphet-
amine.2 Altered biodistribution and behavior toward
metabolic enzymes were among the interesting properties
of these amines. Such amines are indirect-acting, for
example they can act as false neurotransmitters by
displacing the endogenous transmitter from the neuron,
but have no agonist properties themselves. Other effects
can be mediated by blockade of normal re-uptake of the
transmitter into the neuron.
larly attractive targets. We report here a synthesis of â,â-
difluorotryptamines 3a -d and â,â-difluoromelatonin (4)
based on the fluorinative deoxygenation of 3-(2-azi-
doacetyl)indoles. As expected, as the electron density of
the indole ring increases, the reactivity of the fluorine
also increases.
Ch em istr y
We felt that the presence of fluorine on the side chain
of amines that have receptor agonist properties could
have even more profound biological consequences. How-
ever, the reactivity of phenolic benzyl fluorides had
thwarted our attempts, and presumably attempts of
others, to install fluorine at the benzylic position of
catecholamines. In a successful approach to side-chain
fluorinated neurotransmitters, we achieved the synthesis
of â-fluoro- and â,â-difluorohistamine based on Mark-
In our previous work we accomplished the synthesis
of â,â-difluorohistamine by using a double “FBr” addition
strategy to 1-trityl-4-vinylimidazole. Addition of “FBr”,
then elimination of HBr followed by a second “FBr”
addition afforded 1-trityl-4-(2-bromo-1,1-difluoroethyl)-
imidazole that was converted to â,â-difluorohistamine.3
The convenience of this sequence and the ready avail-
ability of 3-vinylindoles encouraged us to use a similar
strategy for the syntheses of fluorinated indolamines. As
a first approach to the parent fluoroinated tryptamine,
N-trityl-3-vinylindole 5a was treated with NBS and
Et3N-3HF to give the desired “FBr” adduct 6a in about
20% yield (by NMR) (Scheme 1). However, all attempts
to separate this material by chromatography failed, due
† These authors made comparable contributions to this research.
(1) (a) Kirk, K. L. J . Fluorine Chem. 1995, 72, 261-266. (b) Kirk,
K. L.; Nie, J .-Y. In Biomedical Frontiers of Fluorine Chemistry; Ojima,
I., McCarthy, J . R., Welch, J . T., Eds.; ACS Symp. Ser.; American
Chemical Society: Washington, DC, 1996; pp 312-327. (c) Kirk, K. L.
In Biomedical Chemistry: Applying Chemical Principles to the Under-
standing and Treatment of Disease; Torrence, P. F., Ed.; J ohn Wiley
& Sons: New York, 1999; pp 247-265.
(2) Fuller, R. W.; Molloy, B. R. In Biochemistry involving carbon-
fluorine bonds; Filler, R., Ed.; ACS Symp. Ser. 28; American Chemical
Society: Washington, DC, 1976; pp 23-36.
(3) Dolensky, B.; Kirk, K. L. J . Org. Chem. 2001, 66, 4687.
(4) Cooper J .; Bloom F.; Roth, R. The Biochemical Basis for Neu-
ropharmacology; Oxford University Press: Oxford, UK, 1991,
10.1021/jo020731c This article not subject to U.S. Copyright. Published 2003 American Chemical Society
Published on Web 03/07/2003
2798 J . Org. Chem. 2003, 68, 2798-2802

Syntheses of â,â-Difluorotryptamines
SCHEME 1 a
a
Reagents: (a) NBS, 3HF-Et3N, CH2Cl2. (b) K2CO3, DMF. (c) NIS, 3HF-Et3N, CH2Cl2. (d) NaN3, DMF.
to the apparent instability of the addition product
6a . On the basis of the assumption that decreasing
the electron density of the indole would lead to greater
stability, we next employed the electronic-withdrawing
phenylsulfonyl group as our indole nitrogen protecting
group. As we hoped, treating 5b with NBS and
Et3N-3HF gave the “FBr” adduct 6b in 50-70% yield.
Elimination of HBr was accomplished by using K2CO3/
DMF to give olefin 7 in 78% yield. The addition of “FBr”
to 7 occurred in good yield, and regiospecifically, to give
2,2-difluoro-2-(3-inodoyl)-1-bromoethane (8) (75%), a key
intermediate in the scheme (Scheme 1). Regrettably, all
attempts to replace bromine with nitrogen functionality,
as was done in our difluorohistamine synthesis, met with
complete failure. For example, treatment of 7 with NaN3
in DMF under a variety of conditions gave no substitution
of bromine by azide. The more reactive iodo compound
was prepared by addition of “FI” to 7 to give 9. The iodo
group was also resistant to displacement by azide.
Furthermore, attempts to displace the halogen with other
nucleophiles, including NH3 (gas), benzenethiol, and
potassium phthalimide, gave disappointing results. This
poor reactivity toward nucleophilic substitution is con-
sistent with the well-documented effects on reactivity
caused by â-fluorine substitution.5 However, decomposi-
tion or side reactions involving the indole nucleus may
have contributed to our failure. In any event, this
approach was abandoned after considerable efforts pro-
duced no promising results.
addition was a more practical route to the more complex
imidazole analogues. Having met with difficulties in this
latter approach as our strategy to synthesize fluorinated
indoles, we now returned to deoxyfluorination as an
alternative. The requirement for installing the side-chain
amine functionality that thwarted the previous approach
in principle could be obviated by carrying out the key
fluorination reaction on a 3-(nitrogen-substituted)acyl
indole. Thus, we explored deoxyfluorination of the N-
protected, appropriately substituted 3-acylindoles.
3-Chloroacetylindole 11a was treated with NaN3 in
aqueous acetone as previously described7to give azido
ketone 12a , which was then converted to the N-Boc
derivative 13a . Reaction of 13a with bis(2-methoxyethyl)-
aminosulfur trifluoride (Deoxo-Fluor)8 at 60 °C gave
smooth fluorination to give the gem-difluoro azidoethyl
compound 14a . The azide was reduced to the amine with
10% Pd-C in MeOH and the Boc group was removed
with gaseous HCl in EtOAc to give the target â,â-difluoro-
tryptamine 3a in good yield as a stable, crystalline
hydrochloride (Scheme 2).
Key indolamines possess oxygen functionality on the
5-position of the indole nucleus.2 We were aware that
increased electron density of the indole ring likely would
increase the reactivity of the benzylic fluorine substitu-
ents. 5-Methoxyindole was acylated with chloroacetyl
chloride to produce chloroketone 11b. As before, this was
converted to the azide and the indole nitrogen was
protected as the Boc amide to give 13b. This was
fluorinated in 75% yield with Deoxo-Fluor (dichloro-
ethane at 75 °C) to produce 14b. Careful reduction of the
azide (10% Pd-C, MeOH) gave the tryptamine 15b in
good yield (Scheme 2). Removal of the Boc group as before
produced â,â-difluoro-5-methoxytryptamine 3b as a stable
In our initial experiments to prepare side-chain fluor-
inated imidazole derivatives, we had prepared fluoro-
methyl and difluoromethyl imidazoles by deoxyfluorina-
tion of N-trityl hydrdoxymethylimidazoles and imidazole
carboxaldehydes.6 Subsequently, we found that the “FBr”
(5) Smart, B. E. In Organofluorine Chemistry, Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J . C.,
Eds.; Plenum: New York, 1994; pp 57-88.
(6) Dolensky, B.; Kirk, K. L. Collect. Czech Chem. Commun. 2002,
67, 1335.
(7) Bergman, J .; Ba¨ckvall, J . E.; Lindstro¨m, J . O. Tetrahedron 1973,
29, 971.
(8) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M.; Cheng, H.
J . Org. Chem. 1999, 64, 7048.
J . Org. Chem, Vol. 68, No. 7, 2003 2799

Deng et al.
SCHEME 2 a
a
Reagents: (a) NaN3, aq acetone. (b) (Boc)2O/NaOH, H2O/THF. (c) Deoxo-Fluoro, 60 °C. (d) Pd/C, H2, MeOH. (e) HCl (gas), EtOAc. (f)
Ac2O, TEA, CH2Cl2, 0 °C.
SCHEME 3
hydrochloride. Acylation of 15b to give 16 followed by
removal of the Boc protecting group gave â,â-difluorome-
latonin 4 (Scheme 2).
Unlike the tryptamines 3a and 3b, which proved to
be quite stable as the hydrochlorides, an NMR sample
â,â-difluoromelatonin 4 in DMSO after overnight storage
in a refrigerator displayed new peaks that appeared to
result from loss of fluorine. A similar conversion was
observed in deuteriomethanol containing triethylamine.
Complete conversion to a new compound could be effected
under these latter conditions. Preliminary data (MS and
NMR) suggest formation of a new heterocylic ring ac-
companied by loss of both fluorine atoms. Since no such
behavior was observed with the nonacylated precursor
we make the assumption that the reactivity is asso-
ciated with the N-acetyl group. One possible mecha-
nism for HF loss to give the new product, tentatively
was fluorinated with Deoxo-Fluor to give the protected
5-benzyloxy tryptamine 14c. Hydrogen over 10% Pd-C
effected hydrogenolysis of the benzyl ether and reduction
of the azide to the amine in one step to give 15d . Removal
identified as 2-methyl-5-[3-(5-methoxyindoyl)]oxazole (17),
of the Boc group by careful treatment of 15d with gaseous
is shown in Scheme 3. A similar transformation is seen
HCl in EtOAc produced the target difluoroserotonin 3d ,
in the formation of 2-methyl-5-[3-(1-acetylindoyl)]oxazole
but this was contaminated by up to 30% with an
from 1-acetyl-3-acetamidoacetylindole by the action of
unidentified product, the NMR spectrum of which sug-
refluxing phosphorus oxychloride. This presumably in-
gested loss of one fluorine. Repeated attempts to increase
volves the loss of two HCl molecules from the gem-di-
purity by lowering the reaction temperature, limiting the
chloro intermediate during a similar cyclization reaction.9
amount of HCl catalyst, and/or changing solvents led to
even less satisfactory results, including lower conversions
and decreased purity. However, a procedure that favored
rapid product formation and precipitation gave excellent
We were particularly eager to prepare â,â-difluoro-5-
hydroxytrytpamine (3d ). The serotonin analogue would
be quite useful to study the effects of amine pKa on such
properties as sertonin transport and receptor binding.
results. Rapid addition of HCl gas to a solution of 15d in
This analogue also proved to be the most difficult to
isolate. 5-Benzyloxyindole was converted to the azido
(9) J oshi, B. S.; Taylor, W. I.; Bhate, D. S.; Karmarkar, S. S.
ketone 13c as described for the previous analogues. This
Tetrahedron 1963, 19, 1437.
2800 J . Org. Chem., Vol. 68, No. 7, 2003

Syntheses of â,â-Difluorotryptamines
mL of acetone was added sodium azide (1.33 g, 20.6 mmol).
The solution was refluxed overnight, and then was diluted with
100 mL of distilled water and extracted with dichloromethane.
The organic layer was dried over anhydrous sodium sulfate
and concentrated at reduced pressure to produce an ivory solid.
The solid was recrystallized in dichloromethane and methanol
to give 1.98 g (97%) of 12a as a pale yellow solid. Mp 181-
183 °C.
SCHEME 4
ter t-Bu tyl 3-(2-Azido-acetyl)-in dole-1-car boxylate (13a).
Di-tert-butyl dicarbonate (581 mg, 2.63 mmol) and 50% aque-
ous NaOH (15 mL) were added to a solution of 12a (440 mg,
2.19 mmol) in 5 mL of THF at 0 °C and the mixture was stirred
for 1 h at ambient temperature. The reaction mixture then
was poured into 100 mL of cooled water and solid precipitate
was removed by filtration, washed with cooled hexane, and
dried in a vacuum to give 348 mg (78%) of 13a as a white solid.
Mp:157-158 °C.
ter t-Bu tyl 3-(2-Azid o-1,1-d iflu or o-eth yl)-in d ole-1-ca r -
boxyla te (14a ). A solution of 13a (253 mg, 0.842 mmol) in 3
mL of bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-
Fluor) was heated at 60 °C overnight. The reaction mixture
was cooled to room temperature and poured into cooled
saturated sodium bicarbonate solution. The solution was
extracted with methylene chloride (30 mL) and the methylene
chloride solution was washed with brine. After being dried over
anhydrous Na2SO4, the solvent was concentrated in vacuo.
Flash column chromatography of the residue on silica gel (10:1
ethyl acetate/hexane) afforded the pure product (14a , 208 mg,
77%) as a pale yellow oil.
ter t-Bu tyl 3-(2-Am in o-1,1-d iflu or o-eth yl)-in d ole-1-ca r -
boxyla te (15a ). A solution of the 14a (128 mg, 0.379 mmol)
in 12 mL of methanol was hydrogenated (balloon) over Pd/C
(10%, 50 mg) for 30 min after which time starting material
had disappeared (TLC). The catalyst was removed by filtration
through Celite and washed with 5 mL of methanol. The filtered
solution was concentrated by rotary evaporation to give a
colorless liquid. The product was purified by flash column
chromatography in 1:1 ethyl acetate/hexane to give 90.7 mg
(77%) of 15a .
a
Purity estimated by using 1H NMR. bNo reaction. cSlight
reaction. dDecomposion.
ether at room temperature led to an almost immediate
precipitate (Scheme 4). Simple evaporation of ether
produced 3d hydrochloride as a homogeneous compound
based on NMR spectra.
It is noteworthy that NMR solutions are not stable,
and 3d is fairly rapidly converted to a new compound
when kept in solution. NMR data again indicate loss of
fluorine. Rapid removal of the Boc group from 15d to give
a critical concentration of 3d sufficient to cause its
efficient precipitation as the stable crystalline form would
seem important to the success of this procedure. The
facile loss of fluoride from 3d revealed by the NMR data
could influence strategies and results of biological studies.
For this reason we are examining the chemistry of 3d in
more detail and will report the results in a subsequent
publication. Included will be a study of stability under
different conditions and characterization of product(s) of
fluoride loss.
Fuller reported that geminal fluorine substitution in
the benzylic position lowered the pKa value of phenyl-
ethylamines by approximately 2 pH units.2 We found a
similar lowering of basicity in â,â-difluorohistamines.3
Attempts to determine titrametric pKa values of 3a have
been unsuccessful to date because of apparent decompo-
sition (color change) at higher pH values.
2,2-Diflu or o-2-(1H-in d ol-3-yl)-eth yla m in e Hyd r och lo-
r id e (3a ). Hydrogen chloride gas was bubbled into a solu-
tion of 15a (90.7 mg, 0.30 mmol) in 10 mL of ethyl acetate for
20 min. The solvent was evaporated to give 3a (55.9 mg,
1
67.6%) as a white solid. Mp 148 °C dec. H NMR (300 MHz,
DMSO-d6) δ 11.77 (1H, br s), 8.69 (2H, br s), 7.80 (1H, s), 7.65
(1H, d, J ) 6.9 Hz), 7.48 (1H, d, J ) 7.2 Hz), 7.13-7.21 (2H,
m), 3.85 (2H, t, J ) 14.4 Hz). 13C NMR (75 MHz, DMSO-d6) δ
138.1, 125.8 (t, J ) 7.9 Hz), 123.5, 122.3, 122.2, 120.7, 120.2,
119.5, 118.9, 112.1, 107.3 (t, J ) 28.6 Hz), 43.3 (t, J ) 29.7
Hz). 19F NMR (281.28 MHz, DMSO-d6) δ -15.87 (t, J ) 15.52
Hz). MS (FAB, M+ + 1) 197.16. Anal. Calcd for C10H10F2N2‚
2HCl: C, 44.64: H, 4.49: N, 10.41. Found: C, 45.74: H, 4.19:
N, 9.57.
2-Ch lor o-1-(5-m eth oxy-1H-in d ol-3-yl)-eth a n on e (11b).
Pyridine (1.65 mL, 20.38 mmol) was added to a solution of
5-methoxyindole (3.0 g, 20.38 mmol) in 15 mL of toluene.
Chloroacetyl chloride (1.61 mL, 20.38 mmol) was added
dropwise at ambient temperature over 30 min and the solution
was then stirred for 1.5 h at 60 °C. After the reaction mixture
was cooled, it was poured into 50 mL of distilled water. The
resulting solid was collected by filtration and recrystallized
from ethanol (40 mL) to give 11b (2.673 g, 59%) as a white
solid. Mp >230 °C.
2-Azid o-1-(5-m eth oxy-1H-in d ol-3-yl)-eth a n on e (12b). To
a solution of 11b (2 g, 8.94 mmol) in 150 mL of acetone/water
(2:1) was added sodium azide (1.342 g, 20.65 mmol). The
reaction mixture was refluxed overnight, then cooled, diluted
with 100 mL of water, and extracted with methylene chlor-
ide (2 × 50 mL). The organic layer was dried over Na2SO4
and evaporated, and the residue was recrystallized from
ethyl acetate to give 12b (1.93 g, 94%) as a white solid. Mp
180 °C.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. 1H,
13C, and 19F NMR spectra were recorded at 300.1, 75.5, and
282.2 MHz. Chemical shifts (δ) of protons and carbons are
relative to TMS (0 ppm), and the fluorine shifts are relative
to trifluoroacetic acid (0 ppm), all in ppm. Interaction constants
are presented in Hz. The solvent is CDCl3 unless otherwise
noted. Low-resolution MS (LRMS) was performed with chemi-
cal ionization under ammonia gas. High-resolution MS (HRMS)
was done with FAB ionization under xenon gas. Silica gel
(0.040-0.063 mm) was used for column chromatography, and
1000 mm silica gel GF plates were used for preparative TLC.
All reagents and dry solvents were purchased if not otherwise
indicated and used without further purification or drying.
2-Azid o-1-(1H-in d ol-3-yl)-eth a n on e (12a ). To a stirred
solution of 11a (2.0 g, 10.3 mmol) in 100 mL of water and 50
J . Org. Chem, Vol. 68, No. 7, 2003 2801

Deng et al.
ter t-Bu tyl 3-(2-Azid o-a cetyl)-5-m eth oxy-in d ole-1-ca r -
boxyla te (13b). Di-tert-butyl dicarbonate (2.87 g, 13.03 mmol)
and 50% NaOH solution (15 mL) were added to a solution of
12b (1.5 g, 6.515 mmol) in 15 mL of THF at 0 °C. The solution
was stirred for 1 h at ambient temperature. The reaction
mixture was poured into 100 mL of cooled water and the
resulting solid was collected by filtration, washed with cooled
hexane, and dried in a vacuum to give 1.975 g (92%) of 13b as
white solid. Mp 162-163 °C.
ter t-Bu tyl 3-(2-Azid o-1,1-d iflu or o-eth yl)-5-m eth oxy-in -
d ole-1-ca r boxyla te (14b). To a solution of 13b (500 mg, 1.51
mmol) in 10 mL of dichloroethane was added 2 mL of Deoxo-
Fluor and the solution was stirred overnight at 60 °C. The
reaction mixture was cooled to room temperature and poured
into cooled saturated sodium bicarbonate solution. The solution
was extracted with methylene chloride (30 mL), washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
in a vacuum. Flash column chromatography of the residue on
silica gel (15:1 ethyl acetate/hexane) afforded pure 14b (338
mg, 73%) as a pale yellow oil.
ter t-Bu t yl 3-(2-Am in o-1,1-d iflu or o-et h yl)-5-m et h oxy-
in d ole-1-ca r boxyla te (15b). A solution of 14b (385 mg, 1.090
mmol) in 20 mL of methanol was hydrogenated (balloon) over
10% Pd/C (150 mg) for 3 h, after which time starting material
had disappeared. The catalyst was removed by filtration
through Celite and washed with 5 mL of methanol. The filtered
solution was concentrated by rotary evaporation to give a
colorless residue. This was subjected to flash column chroma-
tography in 1:1.5 ethyl acetate/hexane to give 15b as a viscous
liquid (275 mg, 77%).
2,2-Diflu or o-2-(5-m eth oxy-1H-in dol-3-yl)-eth ylam in e Hy-
d r och lor id e (3b). Dry HCl gas was bubbled into a solution
of 15b (206 mg, 0.631 mmol) in 15 mL of ethyl acetate for 1 h
while the temperature was maintained at -60 °C. The solution
was then warmed slowly to room temperature. The solvent
was evaporated to give 3b (135 mg, 90%) as a white solid. Mp
>153 °C dec.1H NMR (300 MHz, DMSO-d6) δ 11.6 (1H, br s),
8.64 (2H, br s), 7.73 (1H, s), 7.38 (1H, d, J ) 8.7 Hz), 7.01
(1H, d, J ) 1.5 Hz), 6.85 (1H, dd, J ) 9.0 Hz, 2.4 Hz), 3.85
(2H, t, J ) 14.4 Hz). 13C NMR (75.5 MHz, DMSO-d6) δ 154.1,
131.2, 126.1 (t, J ) 7.99 Hz), 124.1, 119.7 (t, J ) 235.0 Hz),
112.9, 112.4, 107.0 (t, J ) 29.2 Hz), 100.6, 55.4, 43.3 (t, J )
29.2 Hz). 19F NMR (282.18 MHz, DMSO-d6) δ -16.00 (t, J )
15.23 Hz). MS (FAB+) m/z (M + H+) calcd 227.0996, obsd
227.0990
2.1 Hz), 3.94 (2H, td, J ) 14.7, 2.4 Hz), 3.76 (3H, s), 1.85 (3H,
s). 13C NMR (75.5 MHz, DMSO-d6) δ 169.7, 153.9, 131.3, 152.2
(t, J ) 8.0 Hz), 124.6, 121.1 (t, J ) 234.5 Hz), 112.7, 112.2,
109.2 (t, J ) 29.8 Hz), 100.9, 55.3, 43.6 (t, J ) 30.3 Hz). 19F
NMR (282.18 MHz, DMSO-d6) δ -16.07 (t, J ) 15.23 Hz).
Anal. Calcd for C13H14F2N2O2‚HCl: C, 51.24: H, 4.96: N, 9.19.
Found: C, 51.74: H, 4.42: N, 8.30.
5-Meth oxy-3-(2-m eth yl-oxa zol-5-yl)-1H-in d ole (17). A
solution of 4 (10 mg, 0.04 mmol) in 3 mL of MeOH was treated
with a few drop of triethylamine for 5 min at room tempera-
ture. The solvent was evaporated and the crude product was
purified by silica gel column chromatography (ethyl acetate/
hexane 1:2) to give light pink solid 17 (7.9 mg, 81%).
1-(5-Ben zyloxy-1H-in d ol-3-yl)-2-ch lor o-eth a n on e (11c).
11c was prepared by acylation of 5-benzyloxyindole as de-
scribed for the preparation of 11b. Yield 66%; mp >218 °C
dec. 1H NMR (300 MHz, DMSO-d6) δ 12.06 (br s, 1H), 8.37 (d,
1H, J ) 3.3 Hz), 7.76 (d, 1H, J ) 2.1 Hz), 7.32-7.49 (m, 6H),
6.95 (dd, 1H, J ) 8.7, 2.4 Hz), 5.13 (s, 2H), 4.84 (s, 2H). 13C
NMR (75.5 MHz, DMSO-d6) δ 105.9, 154.6, 137.4, 134.9, 131.5,
128.3, 127.6, 127.5, 126.2, 113.5, 113.4, 113.1, 104.4, 69.6, 46.3.
HRMS calcd for C17H14ClNO2 299.0713, found 299.0711.
2-Azid o-1-(5-ben zyloxy-1H-in d ol-3-yl)-eth a n on e (12c).
12c was prepared from 11c as described for the preparation
of 12b. Yield 89%; mp 173-174 °C.
ter t-Bu tyl 3-(2-Azid o-a cetyl)-5-ben zyloxy-in d ole-1-ca r -
boxyla te (13c). Acylation of 12c with Boc anhydride as
described for the preparation of 13a ,b gave 13c. Yield 92%;
mp 155-156 °C.
ter t-Bu tyl Ester 3-(2-Azid o-1,1-d iflu or o-eth yl)-5-ben -
zyloxy-in d ole-1-ca r boxyla te (14c). Fluorination of 13c with
Doxo-Fluor as described for the preparation of 14a ,b gave
14c.Yield 69%; mp 93-94 °C.
ter t-Bu tyl 3-(2-Am in o-1,1-d iflu or o-eth yl)-5-h yd r oxy-in -
d ole-1-ca r boxyla te (15d ). A solution of 14c (287 mg, 6.69
mmol) in 1 mL of THF and 10 mL of methanol was hydroge-
nated (baloon) over 10% Pd/C (150 mg) for 2 h. The catalyst
was removed by filtration through Celite. The filtrate was
concentrated by rotary evaporation and the residue was
purified with silica gel column chromatography to give a white
solid (167 mg). Yield 80%; mp >130 °C dec.
3-(2-Am in o-1,1-d iflu or o-et h yl)-1H -in d ol-5-ol H yd r o-
ch lor id e (3d ). To a solution of 15d (200 mg, 0.64 mmol) in
20 mL of diethyl ether was bubbled anhydrous HCl (g) for 10
min at room temperature. The resulting solid was filtered and
dried over vacuum to give 3d (98 mg, 72%) as a white solid.
Mp >143 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.58 (br s, 1H),
8.05 (br s, 1H), 7.80 (br s, 3H), 6.76 (s, 1H), 6.35 (d, 1H, J )
8.4 Hz), 6.07 (s, 1H), 5.80 (dd, 1H, J ) 8.7, 2.1 Hz), 2.86 (t,
2H, J ) 15.0 Hz). 13C NMR (75.5 MHz, DMSO-d6) δ 151.7,
134.9, 130.6, 125.9 (t, J ) 5.29 Hz), 124.6, 119.8 (t, J ) 235.8
Hz), 112.7, 106.5 (t, J ) 28.7 Hz), 102.9, 43.3 (t, J ) 29.2 Hz).
19F NMR (282.18 MHz, CD3OD) δ -15.8 (t, J ) 12.4 Hz).
HRMS calcd for C10H10F2N2O 212.0761, found 212.0761.
ter t-Bu tyl 3-(2-Acetyla m in o-1,1-d iflu or o-eth yl)-5-m eth -
oxy-in d ole-1-ca r boxyla te (16). To a solution of 15b (275 mg,
0.842 mmol) in 7 mL of methylene chloride were added
triethylamine (0.225 mL, 1.685 mmol) and acetic anhydride
(160 µL, 1.685 mmol) at 0 °C. The reaction mixture was stirred
for an additional 1 h at 0 °C. Removal of the solvent and
purification of the residue by flash chromatography on silica
gel (hexane/EtOAc 1:1) afforded 16 (246 mg, 79%) as a white
solid.
N-[2,2-Diflu or o-2-(5-m eth oxy-1H-in d ol-3-yl)-eth yl]-a c-
eta m id e (â,â-Diflu or om ela ton in ) (4). To a solution of 15b
(238 mg, 0.640 mmol) in 15 mL of ethyl acetate was bubbled
hydrogen chloride gas for 1 h while the temperature was
maintained at -60 °C. The solution was then warmed slowly
to room temperature. Evaporation of the solvent gave 12 (166
mg, quantitative) as gray solid. Mp 121 °C dec. H NMR (300
MHz, DMSO-d6) δ 11.38 (1H, br s), 8.34 (1H, br s), 7.58 (1H,
s), 7.33 (1H, d, J ) 9.0 Hz), 7.08 (1H, s), 6.81 (1H, dd, J ) 9.0,
Su p p or tin g In for m a tion Ava ila ble: Details for the
synthesis and characterization of compounds 6b, 7, 8, and 9;
product characterization data for 12a , 13a , 14a , 15a , 11b, 12b,
13b, 14b, 15b, 16, 17, 11c, 12c, 13c, 14c, and 15d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
J O020731C
2802 J . Org. Chem., Vol. 68, No. 7, 2003