In search of simplicity and flexibility: A rational access to twelve fluoroindolecarboxylic acids

Article abstract of DOI:10.1002/ejoc.200600118

All twelve indolecarboxylic acids 1-12 carrying both a fluorine substituent and a carboxy group at the benzo ring have been prepared either directly from the corresponding fluoroindoles 13-16 or from the chlorinated derivatives 22, 23 and 25 by hydrogen/metal permutation ("metalation"), or from the bromo- or iodofluoroindoles 17-20 and 26, 27, 29 and 30 by halogen/metal permutation, the organometallic intermediate being each time trapped with carbon dioxide. In most, though not all cases, the nitrogen atom in the five-membered ring had to be protected by a trialkylsilyl group. Some of the bromo- or iodofluoroindoles (26 and 27) were successfully subjected to a basicity gradient-driven selective migration of the heavy halogen. An unexpected finding on the way to the target compounds were the rigorously site-selective metalation of the 5-fluoro-N-(trialkylsilyl)indole (14b; exclusive deprotonation of the 4-position). The fluoroindoles 13-16, although previously known, were accessed more conveniently from suitably substituted nitrobenzenes using the Bartoli or the Leimgruber-Batcho method. A new and very attractive indole synthesis was elaborated consisting of the ortho-lithiation of an N-acyl-protected aniline followed by ortho-formylation, Wittig chloromethylenation and base-catalyzed cyclization accompanied by dehydrochlorination. These five consecutive steps can be contracted to a convenient one-pot protocol. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600118

FULL PAPER
DOI: 10.1002/ejoc.200600118
In Search of Simplicity and Flexibility: A Rational Access to Twelve
Fluoroindolecarboxylic Acids
Manfred Schlosser,*[a] Assunta Ginanneschi,[a] and Frédéric Leroux[b]
Keywords: Bartoli reaction / Leimgruber–Batcho reaction / Wittig reaction / Metalation / Halogen/metal permutation /
Isomerization by halogen migration / Protective groups
All twelve indolecarboxylic acids 1–12 carrying both a fluor-
ine substituent and a carboxy group at the benzo ring have
been prepared either directly from the corresponding fluo-
roindoles 13–16 or from the chlorinated derivatives 22, 23
and 25 by hydrogen/metal permutation (“metalation”), or
from the bromo- or iodofluoroindoles 17–20 and 26, 27, 29
and 30 by halogen/metal permutation, the organometallic in-
termediate being each time trapped with carbon dioxide. In
most, though not all cases, the nitrogen atom in the five-
membered ring had to be protected by a trialkylsilyl group.
Some of the bromo- or iodofluoroindoles (26 and 27) were
successfully subjected to a basicity gradient-driven selective
migration of the heavy halogen. An unexpected finding on
the way to the target compounds were the rigorously site-
selective metalation of the 5-fluoro-N-(trialkylsilyl)indole
(14b; exclusive deprotonation of the 4-position). The fluoroin-
doles 13–16, although previously known, were accessed
more conveniently from suitably substituted nitrobenzenes
using the Bartoli or the Leimgruber–Batcho method. A new
and very attractive indole synthesis was elaborated con-
sisting of the ortho-lithiation of an N-acyl-protected aniline
followed by ortho-formylation, Wittig chloromethylenation
and base-catalyzed cyclization accompanied by dehydro-
chlorination. These five consecutive steps can be contracted
to a convenient one-pot protocol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
danseton is taken to suppress nausea and vomiting caused
by cancer chemotherapy and radiotherapy.[3]
Introduction
The synthesis[4–6] of indole derivatives can be classified
by the starting materials required, the practically most im-
portant aspect. The venerable Fischer cyclization uses ar-
ylhydrazines and ketones (or, although rarely, aldehydes) as
the determinant components. Two new bonds, the N–Cα
and the Cβ–Cortho linkage are formed in the same step. This
is equally the case with the Bartoli reaction[7] in the course
of which vinylmagnesium bromide adds nucleophilically to
a nitrosoarene, generated in situ from a nitroarene precur-
sor. If the nitroarene bears a methyl group in the ortho posi-
tion one can apply the expedient Leimgruber–Batcho pro-
cedure.[8] Their almost unrestricted availability puts anilines
The benzo[b]pyrrole ring system is arguably the most fre-
quently occurring heterocyclic motif in natural product
chemistry.[1,2] The indole family comprises numerous prom-
inent representatives such as the essential α-amino acid
tryptophan, its putrefaction product skatole, the plant
growth factor 3-indolylacetic acid (heteroauxin), the neuro-
transmitter serotonin, the pineal gland hormone melatonin,
the Rauwolfia alkaloids reserpin and yohimbin, the Ranun-
culus alkaloid ellipticin, the Nux vomica alkaloid strychnine,
the Claviceps purpurea alkaloid ergotamine and the Cathar-
anthus alkaloid vincristine. Many of such plant metabolites
are highly toxic. However, at the same time they may exhi-
bit valuable medicinal properties. This explains why much
effort is devoted to the development of indole-based drugs
having optimized therapeutic profiles. Thus, for example,
sumatriptan is administered against migraine, pindolol as a
β-adrenergic blocker, indomethacin to treat inflammation
and, in particular, to attenuate rheumatic pain, whereas on-
of course in a privileged position as indole precursors. Two
[9–13]
classical methods, the Berlinerblau–Nordlander
and
the Bischler–Möhlau[14] route, alkylate the amino function
with a side chain containing a protected or unprotected β-
oxo group, which enables an acid catalyst to perform an
intramolecular Friedel–Crafts hydroxyalkylation. Alterna-
tively one may begin with an ortho-acylation of the aniline.
The Sugasawa method [15] employs chloroacetonitrile as the
reagent to obtain a 2-aminoaryl chloromethyl ketone, which
after reduction with sodium borohydride undergoes smooth
cyclization and dehydration. On the other hand, an ortho
and N-doubly-acylated aniline affords also an indole when
treated with McMurry low-valent titanium as demonstrated
[a] Institute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale, BCh,
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
[b] Laboratoire de Stéréochimie (UMR CNRS 7509), Université
Louis Pasteur (ECPM),
25 rue Becquerel, 67087 Strasbourg, France
2956
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Rational Access to Twelve Fluoroindolecarboxylic Acids
FULL PAPER
by A. Fürstner et al.[16–19] N-Acyl-o-toluidines are the typi- above fail with indoles having a naked, i.e. substituent-free,
cal substrates for the Madelung cyclization which requires five-membered ring. Finally, ring-closure by electrophilic at-
elevated temperatures (220–300 °C) unless it is mediated by tack of the β-carbon at an ortho-carbon atom requires the
organometallic bases (e. g. butyllithium) rather than by so- assistance of electron-donating groups and is prevented by
dium amide or potassium tert-butoxide. An attractive modi- electron-withdrawing groups. In other words, although in-
fication has been elaborated by M. Le Corre et al.[20,21] An doles are legion, most of them exhibit familiar structural
ortho-methylnitroarene is consecutively brominated with N- patterns and mechanism-compatible polarities. For exam-
bromosuccinimide and condensed with triphenylphosphane ple, not a single fluoroindolecarboxylic acid harboring both
before the nitro group is reduced and the resulting amino the halogen and the carboxy functionality at the benzo ring
function acylated. Treatment with potassium tert-butoxide is known so far. We decided to make all twelve of them
converts ultimately the phosphonium salt into tri- (compounds 1a–12a).
phenylphosphane oxide and an indole. A final modern
method, disclosed by H. Yamanaka et al., is based on the
Stille coupling of an ortho-bromoaniline with cis-(2-ethoxy-
ethenyl)tributyltin and is terminated by an acid-promoted
cyclization.[22]
This collection of target compounds represents a model
case of regioexhaustive structure variation. It thus can serve
[23]
as an ideal test of the “toolbox methods”
designed to
tackle exactly such kind of problems. The conceptional cor-
nerstone of this bundle of procedures is to introduce an
alkali or alkali-earth metal into any vacant substrate posi-
tion, in the present example into all vacant positions of the
fluoroindole benzo ring. All what then remains to be done
is to combine the resulting intermediates with carbon diox-
ide and to isolate the carboxylic acids 1–12 after neutraliza-
tion.
The most straightforward access to organometallic inter-
mediates (“CM species”, M = metal) is the permutational
hydrogen/metal interconversion (“metalation”) of the corre-
[25]
sponding CH compounds.[24] Fluorobenzene
itself and
fluorotoluenes,[26] fluorobiphenyls,[26] fluorochlorobenzenes
[27]
[28]
and fluoroanisoles
or fluoro(methoxymethoxy)ben-
as well readily undergo metalation at a fluorine-
[29]
zenes
adjacent position. Therefore, our first objective was to in-
troduce selectively lithium or another alkali metal into 4-,
5-, 6- and 7-fluoroindoles (13a–16a).
All these procedures suffer from shortcomings. The prep-
aration of the required starting materials and intermediates
can be lengthy in quite a few cases. Structural limitations
are another concern. Several of the methods described
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Fluoroindoles
methylformamide), chloroolefination [using chloromethyl-
(triphenyl)phosphonium chloride] and potassium tert-but-
oxide mediated cyclization followed by deprotection was
carried out stepwise and also as a one-flask nonstop pro-
cedure. The over-all yield (15–19%) of 7-fluoroindole (16a)
was acceptable in either case.
All benzo-ring-substituted fluoroindoles 13a–16a are
documented in the literature and the 4-, 5- and 6-fluoro
isomers are even commercial. We felt nevertheless com-
pelled to invest time and effort in order to revisit, improve
or redesign known syntheses.
Both 4-fluoroindole [30] and 5-fluoroindole [31] were most
easily obtained by consecutive treatment of 7-bromo-4-fluo-
roindole and 7-bromo-5-fluoroindole (17a and 18a, see be-
low), respectively, with two equiv. of butyllithium and meth-
anol. The satisfactory yields (56 and 46%) confirm that the
NH deprotonation step preceded the halogen/metal permu-
tation as expected.[32,33]
The same ortho-formylation/chloromethylenation/cycli-
zation sequence was applied to the preparation of 5-fluo-
roindole (14a). The over-all yield (19%) was again satisfac-
tory.
The access to the 6-fluoroindole (15a) was also ac-
complished in a one-flask procedure. By applying the
Leimgruber–Batcho method, the commercial 4-fluoro-2-
nitrotoluene was directly converted into the product 15a in
33% yield.
Halofluoroindoles
There is no simpler way to make indoles than by the
Bartoli reaction[7] provided that the nitro compound re-
quired as the starting material is readily available. The other
uncertainty concerns the yields. They are extremely vari-
able, never excellent and sometimes close to zero.
Three bromofluoronitrobenzenes can be purchased.
However, these compounds and certain isomers as well can
be obtained less expensively by oxidation of the corre-
sponding bromofluoroanilines. Four isomeric bromofluo-
ronitrobenzenes were thus prepared and, under Bartoli con-
ditions, treated with excess vinylmagnesium bromide to af-
ford 7-bromo-4-fluoroindole (17a, 52%), 7-bromo-5-fluo-
roindole (18a, 57%), 4-bromo-7-fluoroindole (19a, 34%)
and 5-bromo-7-fluoroindole (20a, 36%).
In contrast, the preparation of the 7-fluoroindole (16a)[7]
proved troublesome. In a first attempt, N-tert-butoxycar-
bonyl (BOC) protected 2-fluoroaniline was lithiated at the
6-position[34] and the intermediate trapped with molecular
iodine. The iodo compound thus formed was subjected to
[35,36]
a Cassar–Sonogashira coupling,
and the resulting
ethinylsilane was simultaneously cyclized and deprotected
to afford the 7-fluoroindole (16a) in 64% yield.
Obviously, the yields of isolated products (34–57%) fall
in the same range regardless whether a small fluorine or a
voluminous bromine atom occupies the position adjacent
to the nitro group. G. Bartoli et al.[7,39,40] have always con-
sidered the presence of a bulky substituent in a nitro-adja-
A major improvement was achieved by replacing the io- cent position as a crucial prerequisite for a successful cycli-
dination by a formylation stage and the acetylide coupling zation step. Steric hindrance emanating from the ortho posi-
by a Wittig chloromethylenation.[37,38] The thus modified tion was believed to reorient the attack of the vinylmagne-
reaction sequence consisting of aniline acylation, ortho-li- sium bromide reagent from the nitrogen to the oxygen atom
thiation (using tert-butyllithium), formylation (using di- of the nitro group and the transient nitroso substrate. How-
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Rational Access to Twelve Fluoroindolecarboxylic Acids
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Although much appreciated, the unexpected regioselec-
tivity in favor of the 4-position was puzzling. Eventually we
discovered an analogy in the literature. N-Silyl-protected 5-
(diethylcarbamoyloxy)indole was reported, without com-
ment nor explanation, to undergo metalation also at the 4-
position.[48] What kind of phenomenon does provide extra
acidification to the 4-position but not to the 6-position?
Our tentative explanation focuses, for one thing, on the nat-
ural tendency of the nonbonding carbanionic electrons to
seek stabilization by expanding beyond their ordinary con-
finements. Thus, they will invade the empty space surround-
ing a small carbo- or heterocycle placed in their vicinity.[49]
At the same time, the pronounced distortion of the benzene
ever, if the reaction mechanism is really single electron-
transfer triggered, as the Italian authors plausibly sur-
mise,[39] the vinyl radical has anyway no other choice than
to combine with an oxygen rather than the nitrogen atom.
Moreover, as G. Köbrich et al. have shown,[41] even nitro-
benzene itself reacts with two equiv. of phenyllithium to
produce quantitatively (two equiv.!) phenol. All in all, the
outcome of the reaction appears to depend not only on the
nature of a given substituent, but among other things, the
temperature and, in particular, the solvent, all factors which
may promote or control the numerous possible side reac-
tions leading to anilines, hydroxylamines, alkenylaryl-
amines, azo and azoxy compounds as by-products.
Further halofluoroindoles were prepared on a totally dif-
ferent route by consecutive lithiation and halogenation of
4-, 5- and 6-fluoroindoles. To avoid the ordinary deproton-
ation of the intrinsically most acidic 2-position,[42–44] the
nitrogen had to be protected by bulky groups, in particular
triisopropylsilyl (TIPS)[45,46] or 2,2-diethylbutanoyl.[47] The
N-TIPS-4-fluoroindole (13b) was readily converted into the
5-bromo and 5-chloro derivatives 21b and 22b and, after
deprotection, into the corresponding indoles 21a and 22a
by consecutive metalation and halogenation.
[50]
[51–54]
hexagon upon deprotonation
or lithiation
causes
relief of strain in a three-, four- or five-membered ring if
annulated in the vicinity of the carbanionic center of the
benzenide due to the widening of the C–C–C angle. The
combination of the two effects increases, for example the
statistically corrected kinetic acidity of biphenylene, relative
to that of benzene, at the 2-position by a factor of 6.2 but
at the 1-position by a factor of 490.[55–57]
σ/π-Polarization presumably acts as an additional acid-
ity-enhancing effect. N-Acyl- or N-nitroso-N-methylamines
readily undergo lithiation of the methyl group.[24,58] The na-
ture of this dipole stabilization has been theoretically inves-
tigated.[59,60] Such σ/π-polarization should also lower the
energy of carbanions if directly attached to an N-silylamino
group and perhaps even if located at a vinylogous site like
the 4-position of N-silylindoles.
When N-TIPS-5-fluoroindole (14b) was subjected to an
analogous series of reactions, the 4-position was substituted
exclusively. Deprotonation of the 6-position occurred only
with N-TIPS-4-chloro-5-fluoroindole (23b) as the substrate,
in other words, after the most reactive site had been
blocked. Under such circumstances, 4,6-dichloro-5-fluo-
roindole (24a) was obtained in 45% over-all yield.
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M. Schlosser, A. Ginanneschi, F. Leroux
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Finally, also the N-TIPS-protected 6-fluoroindole was re-
gioselectively metalated. The 7-position being sterically
screened by the bulky silyl group, deprotonation occurred
solely at the 5-position. Trapping of the organometallic in-
termediate with 1,1,2-trichloro-1,2,2-trifluoroethane, 1,2-di-
bromo-1,1,2,2-tetrafluoroethane and molecular iodine gave,
after deprotection, 5-chloro-6-fluoroindole (25a; 85%), 5-
bromo-6-fluoroindole (26a; 84%) and 6-fluoro-5-iodoin-
dole (27a; 79%).
The 6- and 7-fluoroindole-4-carboxylic acids (2, 54%
and 3, 67%, respectively) were readily produced by the con-
secutive treatment of 6-fluoro-4-iodoindole (30a) and 7-
fluoro-4-bromoindole (19a) with two equiv. of butyllithium
and dry ice. Again, as testified by the high yields, the halo-
gen/metal permutation, even if very fast, is clearly outpaced
by the deprotonation of the NH bonds, which is a diffusion-
controlled process by all evidence.
The N-TIPS-protected 6-fluoro-5-chloroindole 25 can be
lithiated at the 4-position using LITMP (lithium 2,2,6,6-
tetramethylpiperidide) as the base. The organometallic in-
termediate proved perfectly stable as evidenced by its con-
version into the carboxylic acid 28a (75%) by reaction with
dry ice, neutralization and deprotection. In contrast, the
iodo species 27b isomerized by basicity gradient-driven
halogen migration [61,62] to afford the 6-fluoro-4-iodoindole
30 (88%) after neutralization and deprotection. Under sim-
ilar conditions, the N-TIPS-protected 5-bromo-6-fluoroin-
dole 26b underwent the bromine/lithium migration more re-
luctantly. After a reaction time of 6 h followed by neutral-
ization, a 5:1 mixture of, respectively, the 4- and 5-bromo
isomers (26b and 29b) was obtained.
As 4-fluoroindole disposes of just one directly halogen-
adjacent position, the site at which deprotonation of its N-
triisopropylsilyl derivative 13a would occur was unequivo-
cal. In fact, after trapping with carbon dioxide, 4-fluoroin-
dole-5-carboxylic acid (4a, 58%) was formed as the sole
detectable product. The outcome of the metalation of 6-
fluoro-1-(triisopropylsilyl)indole (15b), ultimately providing
6-fluoro-5-carboxylic acid (5a), was also predictable as the
bulky silyl substituent of course effectively screens the 7-
position against any attack of a base (see above).
The 7-fluoroindole-5-carboxylic acid (6a; 57%) was
found to be readily accessible from 5-bromo-7-fluoroindole
(20a). Once more the NH entity could remain unprotected.
Fluoroindolecarboxylic Acids
Whenever it was possible to metalate a fluoroindole or
an N-protected derivative thereof regioselectively, this was
the method of choice to access the corresponding fluoroin-
The 4-fluoroindole-6-carboxylic acid (7a, 82%) was pre-
dolecarboxylic acid. In this way, 5-fluoroindole-4-carbox- pared starting from 5-chloro-4-fluoro-1-(triisopropylsilyl)-
ylic acid (1) was obtained in high yield (74%) and isomer- indole (22b) via the 5-chloro-4-fluoroindole-6-carboxylic
ically pure.
acid (31a, 79%). The role of the chlorine atom was to
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protect the fluorine-adjacent position against lithiation and nitrogen atom spreads out in all directions and deactivates
at the same time to activate the neighboring 6-position to- also the benzo ring toward base attack.
ward deprotonation (“deflected metalation” [23]). The heav-
ier halogen was reductively eliminated using ammonium
formate in methanol as the hydrogen source and palladium
on charcoal as the catalyst.[63]
The halogen/metal permutation of 7-bromo-4-fluoro-
indole (17a) and 7-bromo-5-fluoroindole (18a) proceeded
without any problem and provided the 4-fluoroindole-7-
carboxylic acid (10, 67%) and 5-fluoroindole-7-carboxylic
acid (11, 55%) after carboxylation and neutralization. Once
more, the NH unit could remain unprotected.
Blockage by a chlorine atom was also the key feature
of the synthesis of 5-fluoroindole-6-carboxylic acid (8). As
already specified for acid 31a, the 4-chloro-5-fluoro-6-carb-
oxylic acid (32a, 74%) resulting from metalation, carboxyl-
ation and desilylation was dechlorinated by catalytic hydro-
genation.
Fluoroindole 15a was found to undergo metalation
smoothly at the 7-position (60% of acid 12, after trapping
with dry ice) without prior silylation of the heterocyclic ni-
trogen atom. Apparently the NLi neighboring group assist-
ance outweighs the deactivating electron donation of the
NLi center. All other fluoroindole isomers (13a, 14a, and
16a) had proven totally inert towards organometallic rea-
gents once the NH site was deprotonated and lithiated.
Removal of the chlorine atom, which served as a tempo-
rary protecting group, by catalytic hydrogenation was also
the last step in the preparation of 6-fluoroindole-4-carbox-
ylic acid (2a, 79%) starting from 5-chloro-6-fluoro-1-(triiso-
propylsilyl)indole (25) and passing through 5-chloro-6-
fluoro-1-(triisopropylsilyl)indole-4-carboxylic acid (28; see
above). Acid 2a (71%) had been independently accessed
from 6-fluoro-4-iodoindole (30a), as previously mentioned.
The unique virtue of this organometallic approach to di-
versity-oriented synthesis is its product flexibility. Any
member of the infinite pool of electrophilic reagents may
be selected instead of carbon dioxide in order to open an
entry to other classes of functionalized derivatives. To sup-
port this claim, also several fluorinated 5-hydroxyindoles
and indole-5-carbaldehydes have been prepared.[64]
Experimental Section
Details regarding standard operations and abbreviations can be
found in previous publications from this laboratory.[65–67] 1H, 13C
(1H-decoupled) and 19F NMR spectra of samples dissolved in
deuteriochloroform or, if marked by an asterisk, in hexadeuterio-
acetone were recorded at 400, 101 and 376 MHz, respectively,
chemical shifts being given relative to tetramethylsilane and trichlo-
7-Fluoro-1-(triisopropylsilyl)indole (16b) underwent
smooth metalation at the 6-position to afford, after carbox-
ylation, the 7-fluoroindole-6-carboxylic acid (9, 80%). No
C-deprotonation occurred at all when the free 7-fluoroin-
dole (16a) was treated with two equiv. of sec-butyllithium.
rofluoromethane as the internal standards. Some of the nitrogen-
1
Obviously the electron excess accumulated at the lithiated bound H signals were too broad to be unequivocally identified.
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Fluoroindolecarboxylic Acids
(3.0 mmol) in tetrahydrofuran (6.0 mL) and hexanes (1.9 mL) was
kept for 45 min at –75 °C before being poured on an excess of
freshly crushed dry ice and treated with dilute hydrochloric acid.
Most of the twelve fluoroindolecarboxylic acids were prepared by
consecutive treatment of the fluoroindoles 13–16, whether they
carry a 1-triisopropyl (TIPS) protecting group or not, or of the
bromofluoroindoles 17–20 and iodofluoroindole 30 with butyllith-
ium and dry ice, a few others by metalation of the TIPS-protected
chlorofluoroindoles 22, 23 and 25 followed by carboxylation and
dechlorination. The access to all precursor compounds is described
in the sub-chapters “fluoroindoles”, “halofluoroindoles” and
“chlorofluoroindolecarboxylic acids” appearing below.
7-Fluoroindole-4-carboxylic Acid (3a): At –75 °C, butyllithium
(15 mmol) in hexanes (10 mL) was added to a solution of 4-bromo-
7-fluoroindole (19a, 1.1 g, 5.0 mmol) in tetrahydrofuran (30 mL).
After having been kept for 2 h in a dry ice/methanol bath, the reac-
tion mixture was poured onto an excess of freshly crushed dry ice.
Water was added (50 mL). The organic phase was acidified to pH
1 and extracted with diethyl ether (2×15 mL). The solvents were
evaporated and the residue was crystallized from 75% aqueous
methanol and sublimed; colorless needles; m.p. 203–205 °C; yield:
5-Fluoro-1-(triisopropylsilyl)indole-4-carboxylic Acid (1b): 2,2,6,6-
Tetramethylpiperidine (3.4 mL, 2.8 g, 20 mmol), potassium tert-but-
oxide (2.5 g, 20 mmol) and 5-fluoro-1-(triisopropylsilyl)indole
(14b, 2.9 g, 10 mmol) were added consecutively to a solution of
butyllithium (20 mmol) in tetrahydrofuran (40 mL) and hexanes
(10 mL). After 2 h at –75 °C, the mixture was poured onto an ex-
cess of freshly crushed dry ice. Water was added (10 mL). The or-
ganic phase was decanted and the aqueous one extracted with di-
ethyl ether (3×10 mL). The combined organic layers were washed
1
0.613 g (68%). H NMR*: δ = 11.0 (broad s, 1 H), 7.86 (dd, J =
8.5, 5.1 Hz, 1 H), 7.56 (broad s, 1 H), 7.18 (broad s, 1 H), 6.97 (dd,
J = 10.5, 8.5 Hz, 1 H) ppm. 13C NMR*: δ = 167.2, 159.5 (d, J =
243 Hz), 154.2, 133.7, 127.8, 124.4, 118.1, 105.5 (d, J = 22 Hz),
104.2 ppm. 19F NMR*: δ = –127.8 (dt, J = 11.1, 3.8 Hz) ppm. MS
(c.i.): m/z (%) = 197 (100) [M+ +NH4], 180 (37) [M+ +H], 162 (15),
151 (2). C9H6FNO2 (179.15): calcd. C 60.34, H 3.38; found C
60.53, H 3.45.
with
a 1.0  solution of citric acid (2×15 mL) and brine
(2×10 mL) before the solvents were evaporated. Crystallization
from diethyl ether/hexanes (1: 10) gave colorless cubes; m.p. 131–
133 °C; yield: 2.48 g (74%). 1H NMR: δ = 7.65 (dd, J = 9.0, 4.0 Hz,
1 H), 7.45 (d, J = 3.0 Hz, 1 H), 7.31 (d, J = 3.0 Hz, 1 H), 6.94 (dd,
J = 12.0, 9.0 Hz, 1 H), 1.68 (sept, J = 7.0 Hz, 3 H), 1.14 (d, J =
7.0 Hz, 18 H) ppm. 13C NMR: δ = 170.5, 159.2 (d, J = 255 Hz),
138.0, 135.5, 132.2, 119.7, 110.0 (d, J = 26 Hz), 107.4, 106.5, 18.0
(3 C), 12.2 (6 C) ppm. 19F NMR: δ = –118.3 (d, J = 9 Hz) ppm.
MS (c.i.): m/z (%) = 339 (100) [M+ +4], 311 (3), 294 (49), 250 (5).
C18H26FNO2Si (335.50): calcd. C 64.44, H 7.81; found C 65.02, H
8.45.
4-Fluoro-1-(triisopropylsilyl)indole-5-carboxylic Acid (4b): A solu-
tion containing 4-fluoro-1-(triisopropylsilyl)indole (13b, 4.4 g,
15 mmol) and sec-butyllithium (15 mmol) in cyclohexane (13 mL)
and tetrahydrofuran (30 mL) was kept for 2 h at –75 °C before be-
ing poured onto an excess of freshly crushed dry ice. Water was
added (10 mL). The organic phase was washed with 1.0  solution
of citric acid (2×15 mL) and the solvents evaporated. The residue
was crystallized from a 1:10 (v/v) mixture of diethyl ether and hex-
anes to give colorless cubes; m.p. 155–157 °C; yield: 3.17 g (63%).
1H NMR: δ = 7.80 (t-like dd, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz,
1 H), 7.29 (d, J = 3.0 Hz, 1 H), 6.85 (d, J = 3.0 Hz, 1 H), 1.70
(sept, J = 8.0 Hz, 3 H), 1.14 (d, J = 8.0 Hz, 18 H) ppm. 13C NMR
δ = 170.2, 157.2 (d, J = 256 Hz), 146.7, 132.1, 124.7, 121.0 (d, J =
21 Hz), 109.9, 107.2, 102.4, 18.0 (3 C), 12.7 (6 C) ppm. 19F NMR:
δ = –115.2 (d, J = 7.0 Hz) ppm. MS (c.i.): m/z (%) = 353 (70)
[M+ +NH4], 336 (37) [M+ +1], 318 (11), 292 (30). C18H26FNO2Si
(335.50): calcd. C 64.44, H 7.81; found C 63.41, H 7.73.
5-Fluoroindole-4-carboxylic Acid (1a): At 25 °C, tetrabutylammo-
nium fluoride hydrate (1.3 g, 5.0 mmol) was dissolved in a solution
of 5-fluoro-1-(triisopropylsilyl)-4-indolecarboxylic acid (1b, 1.6 g,
5.0 mmol) in tetrahydrofuran (10 mL). After 5 min at 25 °C, the
mixture was diluted with diethyl ether, the organic phase washed
with brine (2×10 mL), dried and filtered and the solvents were
evaporated. Crystallization from 90% aqueous methanol afforded
colorless platelets; m.p. 225–227 °C; yield: 0.806 g (90%). 1H
NMR*: δ = 10.6 (broad s, 1 H), 7.72 (ddd, J = 8.9, 4.1, 1.0 Hz, 1
H), 7.59 (t, J = 3.1 Hz, 1 H), 7.08 (symm. m, 1 H), 7.05 (dd, J =
11.2, 8.7 Hz, 1 H). 13C NMR*: δ = 167.5, 159.5 (d, J = 247 Hz),
148.7, 135.1, 130.0, 118.5, 111.7 (d, J = 23 Hz), 110.5, 105.1. 19F
NMR*: δ = –119.6 (broad s) ppm. MS (c.i.): m/z (%) = 197 (86)
[M+ +NH4], 180 (100), 161 (11), 136 (43), 126 (13). C9H6FNO2
(179.15): calcd. C 60.34, H 3.38; found C 60.41, H 3.38.
4-Fluoroindole-5-carboxylic Acid (4a): Prepared, analogously as
acid 1a, starting from 4-fluoro-1-(triisopropylsilyl)indole-5-carbox-
ylic acid (4b, 0.67 g, 2.0 mmol); colorless prisms after crystalli-
zation from 90% aqueous methanol; m.p. 225–227 °C; 0.330 g
(92%). 1H NMR*: δ = 10.9 (broad s, 1 H), 7.71 (dd, J = 8.6, 6.9 Hz,
1 H), 7.45 (t-like dd, J = 2.8 Hz, 1 H), 7.32 (dd, J = 8.6, 0.8, 1 H),
6.67 (symm. m, 1 H) ppm. 13C NMR δ = 166.6, 157.6 (d, J =
260 Hz), 142.4, 127.9, 125.4, 118.7 (d, J = 19 Hz), 109.2, 108.7,
99.7. 19F NMR: δ = –114.7 (d, J = 5.9 Hz) ppm. MS (c.i.): m/z (%)
= 197 (100) [M+ +NH4], 180 (26) [M+ +H], 162 (7), 151 (2).
C9H6FNO2 (179.15): calcd. C 60.34, H 3.38; found C 60.28, H 3.46.
6-Fluoroindole-4-carboxylic Acid (2a): Palladium (10%) on char-
coal (0.21 g, 2.0 mmol) was added to a solution of ammonium for-
mate (0.25 g, 4.0 mmol) and 5-chloro-6-fluoro-4-carboxylic acid
(28a, 0.43 g, 2.0 mmol) in methanol (5 mL). After 2 h at 25 °C, the
reaction mixture was filtered through a celite pad and the solvents
evaporated. After crystallization from 75% aqueous methanol, col-
orless needles were collected; m.p. 222–223 °C; yield: 0.322 g
6-Fluoro-1-(triisopropylsilyl)indole-5-carboxylic Acid (5b): Prepared,
analogously as acid 4b, starting from 6-fluoro-1-triisopropylsilylin-
dole (15b, 1.5 g, 5.0 mmol); colorless cubes after crystallization
from a 1:10 (v/v) mixture of diethyl ether and hexanes; m.p. 167–
(90%). 1H NMR*: δ = 10.6 (broad s, 1 H), 7.61 (dd, J = 10.5, 169 °C; yield: 1.33 g (79%). H NMR: δ = 8.36 (d, J = 7.6 Hz, 1
1
2.5 Hz, 1 H), 7.53 (t, J = 3.2 Hz, 1 H), 7.48 (dd, J = 8.9, 2.4 Hz, 1
H), 7.33 (d, J = 3.2 Hz, 1 H), 7.25 (d, J = 12.9 Hz, 1 H), 6.71 (d,
H), 7.14 (symm. m, 1 H) ppm. 13C NMR*: δ = 169.2, 160.7 (d, J J = 3.2 Hz, 1 H), 1.71 (sept, J = 7.6 Hz, 3 H), 1.15 (d, J = 7.6 Hz,
= 235 Hz), 139.1, 129.5, 126.7, 124.2, 112.2 (d, J = 25 Hz), 105.2,
18 H) ppm. 13C NMR 13C NMR: δ = 170.2, 157.2 (d, J = 256 Hz),
104.1 (d, J = 29 Hz) ppm. MS (c.i.): m/z (%) = 197 (86) [M+ +NH4], 146.7, 132.1, 124.7, 121.0 (d, J = 21 Hz), 109.9, 107.2, 102.4, 18.0
180 (100) [M+ +H], 162 (17), 151 (3), 134 (5), 107 (3). C9H6FNO2 (3 C), 12.7 (6 C) ppm. 19F NMR: δ = –118.3 (dd, J = 12.4, 7.1 Hz)
(179.15): calcd. C 60.34, H 3.38; found C 60.38, H 4.44. The same
acid 2a was obtained in 54% yield (0.096 g) when a solution of 6-
fluoro-4-iodoindole (30a, 0.26 g, 1.0 mmol) and butyllithium
ppm. MS (c.i.): m/z (%) = 353 (0) [M+ +NH4], 336 (100) [M+ +1],
292 (30), 248 (5), 206 (2). C18H26FNO2Si (335.50): calcd. C 64.44,
H 7.81; found C 63.44, H 7.60.
2962
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2956–2969

Rational Access to Twelve Fluoroindolecarboxylic Acids
FULL PAPER
6-Fluoroindole-5-carboxylic Acid (5a): Prepared, analogously as
acid 1a, starting from 6-fluoro-1-(triisopropylsilyl)indole-5-carbox-
ylic acid (5b, 0.67 g, 2.0 mmol); colorless cubes (from 90% aqueous
11.1 (broad s, 1 H), 7.71 (m, 2 H), 7.52 (d, J = 8.6 Hz, 1 H), 6.71
(td, J = 2.9, 1.7 Hz, 1 H) ppm. 13C NMR*: δ = 167.2, 151.5 (d, J
= 260 Hz), 137.2, 130.7, 126.0 (d, J = 16 Hz), 123.2, 117.2, 111.2,
104.5 ppm. 19F NMR*: δ = –129.6 (s) ppm. MS: m/z (%) = 193
(37) [M+ +NH4], 179 (100) [M+ +1], 162 (37), 149 (6), 134 (13).
C9H6FNO2 (179.15): calcd. C 60.34, H 3.38; found C 60.41, H 3.44.
1
methanol); m.p. 230–231 °C; yield: 0.322 g (90%). H NMR*: δ =
10.9 (broad s, 1 H), 8.29 (d, J = 7.1 Hz, 1 H), 7.45 (dd, J = 3.4,
2.3 Hz, 1 H), 7.24 (dd, J = 12.1, 0.9 Hz, 1 H), 6.64 (symm. m, 1
H) ppm. 13C NMR δ = 167.2, 160.7 (d, J = 250 Hz), 140.5, 129.1,
126.7, 126.1, 112.9, 104.5, 99.9 (d, J = 31 Hz) ppm. 19F NMR: δ
= –118.9 (dd, J = 12.1, 7.0 Hz) ppm. MS (c.i.): m/z (%) = 197 (20)
[M+ +NH4], 179 (100) [M+], 162 (43), 134 (18), 121 (9), 107 (16),
99 (8), 81 (12). C9H6FNO2 (179.15): calcd. C 60.34, H 3.38; found
C 60.41, H 3.44.
4-Fluoroindole-7-carboxylic Acid (10a): Prepared, analogously as
acid 3a, from 7-bromo-4-fluoroindole (17a, 2.1 g, 10 mmol) and
purified by sublimation; colorless needles; m.p. 227–228 °C; yield:
1.20 g (67%). 1H NMR*: δ = 10.8 (broad s, 1 H), 7.91 (dd, J =
8.5, 5.3 Hz, 1 H), 7.50 (t-like dd, J = 2.8 Hz, 1 H), 6.89 (dd, J =
10.2, 8.5 Hz, 1 H), 6.66 (dd, J = 3.4, 2.3 Hz, 1 H) ppm. 13C NMR*:
δ = 169.1, 161.1 (d, J = 252 Hz), 140.5, 128.5, 128.1 (d, J = 9 Hz),
119.2, 112.0, 105.7, 99.5 ppm. 19F NMR*: δ = –114.2 (m) ppm.
MS (c.i.): m/z (%) = 179 (100) [M+], 161 (97), 135 (33). C9H6FNO2
(179.15): calcd. C 60.34, H 3.38; found C 60.34, H 3.26.
7-Fluoroindole-5-carboxylic Acid (6a): Prepared, analogously as
acid 3a, starting from 5-bromo-7-fluoroindole (20a, 1.1 g,
5.0 mmol) and purified by sublimation; colorless needles; m.p. 227–
1
228 °C; yield: 0.520 g (58%). H NMR*: δ = 10.6 (broad s, 1 H),
8.26 (s, 1 H), 7.62 (d, J = 1.4 Hz, 1 H), 7.56 (dd, J = 5.5, 1.6 Hz,
1 H), 6.75 (dt, J = 2.6, 1.9 Hz, 1 H) ppm. 13C NMR*: δ = 168.7,
151.1 (d, J = 245 Hz), 133.2, 129.3, 128.5, 124.3, 121.2, 108.7 (d, J
= 24 Hz), 105.7 ppm. 19F NMR: δ = –135.1 (dd, J = 12.1, 3.0 Hz)
ppm. MS (c.i.): m/z (%) = 195 (2) [M+ +NH4], 179 (100) [M+], 162
(40), 134 (38), 122 (4), 107 (23), 95 (7), 81 (5). C9H6FNO2 (179.15):
calcd. C 60.34, H 3.38; found C 60.35, H 3.45.
5-Fluoroindole-7-carboxylic Acid (11a): Prepared, analogously as
acid 4b, from 7-bromo-5-fluoroindole (18a, 7.0 g, 33 mmol). The
residue was crystallized from 75% aqueous ethanol affording color-
1
less needles; m.p. 210–212 °C; yield: 3.19 g (54%). H NMR*: δ =
10.6 (broad s, 1 H), 7.72 (dd, J = 9.0, 2.5 Hz, 1 H), 7.66 (dd, J =
9.8, 2.5 Hz, 1 H), 7.61 (t, J = 2.8 Hz, 1 H), 6.68 (t, J = 2.7 Hz, 1
H) ppm. 13C NMR*: δ = 168.7 (d, J = 232 Hz), 158.1, 134.2, 132.0,
129.9, 115.5 (d, J = 20 Hz), 113.1 (d, J = 15 Hz), 112.5, 103.5 ppm.
19F NMR*: δ = –125.7 (t, J = 8.0 Hz) ppm. MS (c.i.): m/z (%) =
179 (100) [M+], 161 (89), 134 (12). C9H6FNO2 (179.15): calcd. C
60.34, H 3.38; found C 60.20, H 3.47.
4-Fluoroindole-6-carboxylic Acid (7a): Prepared, analogously as
acid 2a, from 5-chloro-4-fluoro-6-carboxylic acid (31a, 0.43 g,
2.0 mmol) in methanol (5 mL); colorless needles (from 75% aque-
1
ous methanol); m.p. 215–217 °C; yield: 0.290 g (81%). H NMR*:
δ = 10.8 (broad s, 1 H), 7.72 (dd, J = 8.6, 6.9, 1 H), 7.47 (t, J =
2.6, 1 H), 7.33 (d, J = 8.5, 1 H), 6.70 (symm. m, 1 H) ppm. 13C
NMR*: δ = 157.7, 158.5 (d, J = 262 Hz), 143.5, 128.7, 128.2, 126.5,
110.2, 109.3, 109.1 ppm. 19F NMR*: δ = –116.1 (d, J = 5.0 Hz)
ppm. MS (c.i.): m/z (%) = 179 (84) [M+], 163 (100), 151 (4), 135
(92), 122 (4), 107 (21), 86 (6). C9H6FNO2 (179.15): calcd. C 60.34,
H 3.38; found 60.43, H 3.50.
6-Fluoroindole-7-carboxylic Acid (12a): Potassium tert-butoxide
(2.2 g, 20 mmol) and 6-fluoroindole (15a, 1.3 g, 10 mmol) were
consecutively added to a solution of butyllithium (20 mmol) in hex-
anes (13 mL) and tetrahydrofuran (40 mL) kept in a dry ice/meth-
anol bath. After 2 h at –75 °C the mixture was poured on an excess
of freshly crushed carbon dioxide. Water was added (20 mL), the
aqueous phase decanted and washed with diethyl ether (3×20 mL)
before being acidified to pH 1 and extracted with diethyl ether
(3×25 mL). The combined organic layers were dried, filtered and
the solvents evaporated. Sublimation afforded colorless needles;
5-Fluoroindole-6-carboxylic Acid (8a): Prepared, analogously as
acid 2a, from 4-chloro-5-fluoroindole-6-carboxylic acid (32a, 1.1 g,
5.0 mmol); colorless needles (from 90% aqueous methanol); m.p.
1
215–217 °C; yield: 0.806 g (90%). H NMR*: δ = 11.8 (broad s, 1
1
m.p. 185–187 °C; yield: 1.07 g (60%). H NMR*: δ = 10.7 (broad
H), 8.32 (d, J = 6.4, 1 H), 7.48 (symm. m, 1 H), 7.20 (d, J = 11.6,
1 H), 6.43 (symm. m, 1 H) ppm. 13C NMR*: δ = 168.5, 157.2 (d,
J = 240 Hz), 133.2, 131.2, 129.8, 120.1, 115.2, 106.1 (d, J = 23 Hz),
102.3 ppm. 19F NMR*: δ = –116.2 (dd, J = 6.9, 3.1 Hz) ppm. MS
(c.i.): m/z (%) = 179 (52) [M+], 162 (40), 142 (100), 134 (13), 100
(9). C9H6FNO2 (179.15): calcd. C 60.34, H 3.38; found C 59.68, H
3.67.
s, 1 H), 7.83 (dd, J = 8.7, 4.8 Hz, 1 H), 7.44 (t, J = 2.5 Hz, 1 H),
6.94 (dd, J = 11.9, 8.6 Hz, 1 H), 6.56 (symm. m, 1 H) ppm. 13C
NMR*: δ = 167.1, 160.3 (d, J = 256), 137.1, 127.5 (2 C), 126.6,
109.2 (d, J = 29 Hz), 102.9, 101.8 ppm. 19F NMR*: δ = –115.6 (m)
ppm. MS (c.i.): m/z (%) = 197 (68) [M+ +NH4], 180 (100) [M+ +1],
162 (13), 152 (3), 136 (6). C9H6FNO2 (179.22): calcd. C 60.34, H
3.37; found C 60.64, H 3.40.
7-Fluoro-1-(triisopropylsilyl)indole-6-carboxylic Acid (9b): Prepared,
analogously as acid 4b, from 7-fluoro-1-(triisopropylsilyl)indole
(16b) (1.4 g, 5.0 mmol); colorless cubes after crystallization from a
1: 10 (v/v) mixture of diethyl ether and hexanes; m.p. 167–169 °C;
Fluoroindoles
The 5- and 7-fluoroindoles were obtained starting from the corre-
sponding tert-butyl N-(fluorophenyl)carbamates. The preparation
of these intermediates and derivatives thereof is described in a sub-
chapter following directly below.
1
yield: 1.49 g (89%). H NMR: δ = 7.76 (dd, J = 9.2, 8.1 Hz, 1 H),
7.51 (d, J = 3.2 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 6.55 (d, J =
3.4 Hz, 1 H), 1.75 (sept, J = 7.2 Hz, 3 H), 1.15 (d, J = 7.9 Hz, 18
H) ppm. 13C NMR δ = 171.2, 151.7 (d, J = 248 Hz), 139.7, 136.2,
128.2 (d, J = 12 Hz), 123.0, 115.7, 109.0, 105.7, 18.2 (3 C), 13.5 (6
C) ppm. 19F NMR: δ = –119.6 (s) ppm. MS (c.i.): m/z (%) = 353
(39) [M+ +NH4], 336 (100) [M+ +1], 318 (5), 292 (15), 274 (7), 248
(15), 206 (9), 178 (7). C18H26FNO2Si (335.50): calcd. C 64.44, H
7.81; found C 64.44, H 7.62.
4-Fluoroindole (13a): 7-Bromo-4-fluoroindole (17a, 2.1 g, 10 mmol)
was added to a solution of butyllithium (20 mmol) in hexanes
(16 mL) and tetrahydrofuran (0.10 L) kept in a dry ice/methanol
bath. After 15 min at –75 °C, the mixture was treated+25 °C with
water (10 mL). The organic phase was evaporated. Steam distil-
lation furnished a white solid; m.p. 24–25 °C (ref.[15,68] 25–28 °C);
1
yield: 0.757 g (56%). H NMR: δ = 8.4 (broad s, 1 H), 7.20 (m, 2
7-Fluoroindole-6-carboxylic Acid (9a): Prepared, analogously as
acid 1a, from 7-fluoro-1-(triisopropylsilyl)indole-6-carboxylic acid
(9b, 1.7 g, 5.0 mmol); tiny colorless needles (from 90% aqueous
H), 7.10 (ddd, J = 13.4, 9.6, 4.6 Hz, 1 H), 6.79 (dd, J = 10.9, 8.1 Hz,
1 H), 6.64 (symm. m, 1 H) ppm. 13C NMR*: δ = 160.3 (d, J =
247 Hz), 139.0, 124.5, 123.0, 117.5 (d, J = 14 Hz), 107.5, 104.7,
99.0 ppm. MS (c.i.): m/z (%) = 136 (100) [M+ + H], 124 (5), 108
1
methanol); m.p. 160–162 °C; yield: 0.824 g (92%). H NMR*: δ =
Eur. J. Org. Chem. 2006, 2956–2969
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2963

M. Schlosser, A. Ginanneschi, F. Leroux
FULL PAPER
(21), 81 (4). C8H6FN (135.14): calcd. C 71.10, H 4.48; found C
71.06, H 4.60.
124.5, 121.5, 108.7 (d, J = 29 Hz), 102.7, 97.0 (d, J = 27 Hz) ppm.
MS (c.i.): m/z (%) = 136 (100) [M+ +H], 124 (10), 108 (27), 81 (6).
C8H6FN (135.14): calcd. C 71.10, H 4.48; found C 71.00, H 4.90.
4-Fluoro-1-(triisopropylsilyl)indole (13b): At –75 °C, 4-fluoroindole
(13a, 2.7 g, 20 mmol) and chlorotriisopropylsilane (2.6 mL, 3.8 g,
20 mmol) were added consecutively to a solution of butyllithium
(20 mmol) in hexanes (15 mL) and tetrahydrofuran (40 mL). After
15 min at +25 °C, the mixture was partitioned between water
(20 mL) and diethyl ether (3×10 mL). The combined organic layers
were washed with brine (2×10 mL). Distillation afforded a viscous
yellow oil; b.p. 115–117 °C/0.2 Torr; yield: 5.21 g (89%). 1H NMR:
δ = 7.30 (d, J = 8.1 Hz, 1 H), 7.23 (d, J = 3.0 Hz, 1 H), 7.06 (m, 1
H), 6.78 (dd, J = 11.0, 2.5 Hz, 1 H), 6.71 (d, J = 3.0 Hz, 1 H), 1.70
(sept, J = 8.0 Hz, 3 H), 1.12 (d, J = 8.0 Hz, 18 H) ppm. 13C NMR
δ = 156.3 (d, J = 246 Hz), 143.5, 130.9, 121.5, 120.3, 109.9, 104.5
(d, J = 19 Hz), 100.5, 18.0 (3 C), 12.4 (6 C) ppm. 19F NMR: δ =
–136.4 (dd, J = 10.0, 5.0 Hz) ppm. MS (c.i.): m/z (%) = 292 (100)
[M+ +H], 268 (24), 248 (42), 206 (12), 174 (8), 147 (12), 130 (20),
102 (8). C17H26FNSi (291.49): calcd. C 70.05, H 8.99; found C
69.49, H 8.86.
6-Fluoro-1-(triisopropylsilyl)indole (15b): Prepared, analogously as
4-fluoro-1-(triisopropylsilyl)indole (13b), from 6-fluoroindole (15a,
1.3 g, 10 mmol). The product was isolated after distillation as a
1
viscous yellow oil; b.p. 232–233 °C/2 Torr; yield: 2.13 g (73%). H
NMR: δ = 7.54 (dd, J = 9.6, 5.9 Hz, 1 H), 7.24 (d, J = 3.2 Hz, 1
H), 7.19 (dd, J = 10.9, 2.1 Hz, 1 H), 6.91 (td, J = 11.1, 2.2 Hz, 1
H), 6.61 (d, J = 3.6 Hz, 1 H), 1.69 (sept, J = 7.6 Hz, 3 H), 1.15 (d,
J = 7.6 Hz, 18 H) ppm. 13C NMR δ = 159.7 (d, J = 210), 141.1,
131.5, 128.2, 120.7, 108.5 (d, J = 27 Hz), 104.7, 100.2 (d, J =
29 Hz), 18.2 (3 C), 12.7 (6 C) ppm. 19F NMR: δ = –122.2 (dt, J =
9.1, 6.1 Hz) ppm. MS (c.i.): m/z (%) = 292 (100) [M+ +H], 265 (10),
248 (31), 206 (5), 178 (4). C17H26FNSi (291.49): calcd. C 70.05, H
8.99; found C 70.37, H 9.19.
7-Fluoroindole (16a): A solution of tert-butyl 6-fluoro-2-[(trimethyl-
silyl)ethynyl]phenylcarbamate (7.7 g, 25.0 mmol) and potassium
tert-butoxide (8.4 g, 75.0 mmol) in anhydrous tert-butyl alcohol
(20 mL) was heated to reflux for 5 h. The product was isolated by
steam distillation and extracted with dichloromethane (3×0.10 L);
colorless needles; m.p. 60–62 °C (ref:[68] 61–62 °C); yield: 2.16 g
(64%). 1H NMR: δ = 8.4 (broad s, 1 H), 7.41 (d, J = 8.1 Hz, 1 H),
7.21 (t, J = 3.2 Hz, 1 H), 7.02 (ddd, J = 13.1, 8.4, 4.5 Hz, 1 H),
6.91 (dd, J = 11.5, 8.1 Hz, 1 H), 6.59 (symm. m, 1 H) ppm. 13C
NMR δ = 149.5 (d, J = 237 Hz), 131.7, 125.0, 124.5, 119.7, 116.5,
107.0 (d, J = 19 Hz), 103.5 ppm. MS (c.i.): m/z (%) = 153 (7)
[M+ +NH4], 136 (100) [M+ +H], 124 (12), 108 (35). C8H6FN
(135.14): calcd. C 71.10, H 4.48; found C 71.50, H 4.60. 7-Fluoroin-
dole (16a) was also produced, analogously as described for 5-fluo-
roindole (14a), from tert-butyl 2-[(E)-2-chloroethenyl]-6-fluoro-
phenylcarbamate (5.3 g, 25 mmol) in a yield of 1.25 g (37%) and,
analogously as described for 4-fluoroindole (13a), from 4-bromo-
7-fluoroindole (19a, 5.4 g, 25 mmol) in a yield of 2.53 g (75%).
5-Fluoroindole (14a): A solution containing tert-butyl 2-[(E)-2-chlo-
roethenyl]-4-fluorophenyl-carbamate (see paragraph c of the fol-
lowing Section; 7.7 g, 25 mmol) and potassium tert-butoxide (8.4 g,
75 mmol) in anhydrous tert-butyl alcohol (40 mL) was heated for
5 h at +80 °C. Upon steam distillation a colorless solid was col-
lected and dried in a desiccator; m.p. 46–47 °C (ref.[8,68] 46–47 °C);
yield: 1.55 g (46%). 1H NMR: δ = 8.3 (broad s, 1 H), 7.3 (m, 2 H),
7.21 (t, J = 3.2 Hz, 1 H), 6.95 (ddd, J = 12.1, 9.4, 3.7 Hz, 1 H),
6.51 (symm. m, 1 H) ppm. 13C NMR δ = 158.2 (d, J = 235 Hz),
132.5, 128.5, 126.0, 111.7, 110.2 (d, J = 25 Hz), 105.5 (d, J =
23 Hz), 102.5 ppm. MS (c.i.): m/z (%) = 136 (100) [M+ +1], 124 (2),
107 (8), 87 (3), 76 (4). C8H6FN (135.14): calcd. C 71.10, H 4.48;
found C 71.61, H 4.50. 5-Fluoroindole (14a) was also obtained,
analogously as 4-fluoroindole (13a), starting from 7-bromo-5-fluo-
roindole (18a, 5.5 g, 25 mmol); m.p. 46 47 °C; yield: 1.61 g (48%).
5-Fluoro-1-(triisopropylsilyl)indole (14b): Prepared, analogously as
4-fluoro-1-(triisopropylsilyl)indole (13b), from 5-fluoroindole (14a,
1.3 g, 10 mmol). The product was isolated by distillation as a vis-
cous oil; b.p. 121–123 °C/0.4 Torr; yield: 2.71 g (93%). 1H NMR: δ
= 7.41 (dd, J = 9.0, 4.5 Hz, 1 H), 7.27 (d, J = 3.0 Hz, 1 H), 7.25
(dd, J = 6.9, 2.9 Hz, 1 H), 6.90 (dt, J = 9.0, 3.0 Hz, 1 H), 6.58 (d,
J = 3.0 Hz, 1 H), 1.69 (sept, J = 8.0 Hz, 3 H), 1.12 (d, J = 8.0 Hz,
18 H) ppm. 13C NMR δ = 157.8 (d, J = 210 Hz), 137.2, 132.9,
131.9, 114.2, 109.5 (d, J = 24 Hz), 105.2 (d, J = 23 Hz), 104.8, 18.0
(3 C), 12.8 (6 C) ppm. 19F NMR: δ = –126.0 (symm. m) ppm. MS
(c.i.): m/z (%) = 309 (100) [M+ +NH4+], 292 (98) [M+ +1], 274 (19),
248 (31), 210 (18), 192 (13). C17H26FNSi (291.49): calcd. C 70.05,
H 8.99; found C 70.22, H 9.00.
7-Fluoro-1-(triisopropylsilyl)indole (16b): Prepared, analogously as
7-fluoro-1-(triisopropylsilyl)indole (13b), from 7-fluoroindole (16a,
1.3 g, 10 mmol). The product was isolated after distillation as a
1
viscous oil; b.p. 121–123 °C/1 Torr; yield: 2.80 g (96%). H NMR:
δ = 7.41 (d, J = 7.0 Hz, 1 H), 7.34 (d, J = 2.8 Hz, 1 H), 7.03 (ddd,
J = 14.1, 9.1, 5.2 Hz, 1 H), 6.88 (dd, J = 7.6, 3.4 Hz, 1 H), 6.64 (t,
J = 3.8 Hz, 1 H), 1.71 (sept, J = 7.4 Hz, 3 H), 1.14 (d, J = 7.4 Hz,
18 H) ppm. 13C NMR δ = 150.2 (d, J = 247 Hz), 136.0, 132.5,
128.3, 120.2, 116.5, 107.5 (d, J = 24 Hz), 105.2, 18.5 (3 C), 13.5 (6
C) ppm. 19F NMR: δ = –126.1 (d, J = 13 Hz) ppm. MS (c.i.):
m/z (%) = 292 (100) [M+], 260 (12), 248 (19), 223 (4), 188 (57), 171
(24), 146 (15), 132 (27), 104 (3). C17H26FNSi (291.49): calcd. C
70.05, H 8.99; found C 70.01, H 9.09.
6-Fluoroindole (15a): A solution of dimethylformamide dimethyl
tert-Butyl N-(Fluorophenyl)carbamates and Derivatives Thereof
acetal (40 mL, 36 g, 0.30 mol), pyrrolidine (12 mL, 11 g, 0.15 mol)
a) tert-Butyl N-(4-Fluorophenyl)carbamate: A solution of 4-fluoro-
aniline (19 mL, 22 g, 0.20 mol) and di-tert-butyl dicarbonate (65 g,
0.30 mol) in anhydrous toluene (0.20 L) was heated to reflux for
2 h. The mixture was evaporated and the residue crystallized from
hexanes; colorless needles; m.p. 124–126 °C (ref.[34] m.p. 125–
126 °C); yield: 35.4 g (84%). 1H NMR: δ = 7.31 (dd, J = 8.4,
4.6 Hz, 2 H), 6.95 (t, J = 8.9 Hz, 2 H), 6.5 (broad s, 1 H), 1.51 (s,
9 H) ppm. 13C NMR δ = 199.9 (2 C), 159.1 (d, J = 240), 153.7,
134.5, 119.9, 115.7 (d, J = 26 Hz, 2 C), 28.2 (3 C) ppm. MS (c.i.):
m/z (%) = 229 (41) [M+ +NH4], 212 (66) [M+ +1], 173 (61), 156
(19), 137 (6), 156 (19), 137 (6), 111 (100).
[69]
and 4-fluoro-1-methyl-2-nitrobenzene
(17 g, 0.15 mol) in di-
methylformamide (0.30 L) was heated under reflux for 6 h. At
+25 °C, the reaction mixture was diluted with diethyl ether
(0.10 L), washed with brine (3×25 mL) and the solvents evapo-
rated. The residue was dissolved in 80% aqueous acetic acid
(0.30 L). Zinc powder (49 g, 0.75 mol) was added over a period of
1 h under vigorous stirring before the mixture was heated for 5 h
at 100 °C. Evaporation and steam distillation afforded colorless
platelets; m.p. 74–76 °C (ref.[8,68] 75–76 °C); yield: 6.69 g (33%). 1H
NMR (400 MHz, CDCl3): δ = 8.0 (broad s, 1 H), 7.54 (dd, J = 8.6,
5.4 Hz, 1 H), 7.11 (dd, J = 3.0, 1.7 Hz, 1 H), 7.02 (dd, J = 10.1,
2.4, Hz, 1 H), 6.90 (ddd, J = 11.1, 8.6, 3.1 Hz, 1 H), 6.51 (symm.
m, 1 H) ppm. 13C NMR δ = 160.0 (d, J = 246 Hz), 136.0, 125.2,
b) tert-Butyl N-(4-Fluoro-2-formylphenyl)carbamate: A solution of
[34]
tert-butyl N-(4-fluorophenyl)carbamate
(21 g, 0.10 mol) and
2964
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2956–2969

Rational Access to Twelve Fluoroindolecarboxylic Acids
FULL PAPER
tert-butyllithium (0.20 mol) in tetrahydrofuran (0.20 L) and pen-
tanes (70 mL) was kept 3 h at –50 °C before dimethylformamide
(7.7 mL, 7.3 g, 0.10 mol) was added. When at +25 °C, the mixture
was washed with brine (2×0.10 L) and the solvents evaporated.
Sublimation afforded tiny colorless prisms; m.p. 58–60 °C; yield:
17.0 g (71%). 1H NMR: δ = 7.7 (broad s, 1 H), 7.51 (d, J = 8.3 Hz,
1 H), 7.42 (t, J = 8.7 Hz, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 6.6 (broad
s, 1 H), 1.55 (s, 9 H) ppm. 13C NMR δ = 187.8, 157.2 (d, J = 245),
153.2, 138.2, 123.5 (d, J = 20 Hz), 121.7, 120.5 (d, J = 25 Hz),
120.3, 81.2, 28.0 (3 C) ppm. 19F NMR: δ = –121.8 (dd, J = 12.3,
7.1 Hz) ppm. MS (c.i.): m/z (%) = 257 (41) [M+ +NH4], 240 (100)
[M+ +H], 201 (70), 184 (45), 139 (48). C12H14FNO3 (239.25): calcd.
C 60.24, H 5.90; found C 60.33, H 5.99.
J = 13.4 Hz, 1 H), 6.57 (d, J = 13.2, Hz, 1 H), 6.2 (broad s, 1 H),
1.52 (s, 9 H) ppm. 13C NMR δ = 159.7 (d, J = 246 Hz), 153.2,
130.7, 127.7, 124.7, 122.1, 115.9, 115.7 (d, J = 29 Hz), 113.2 (d, J
= 27 Hz), 81.7, 28.1 (3 C) ppm. MS (c.i.): m/z (%) = 289 (11)
[M+ +NH4], 272 (2) [M+ +1], 233 (100), 216 (22), 171 (39), 136 (28),
111 (8). C13H15ClFNO2 (271.72): calcd. C 57.46, H 5.56; found C
57.20, H 5.70.
g) tert-Butyl (6-Fluoro-2-iodophenyl)carbamate: At dry-ice tempera-
ture, tert-butyllithium (0.10 mmol) in pentane (75 mL) was added
to a solution of tert-butyl N-(2-fluorophenyl)carbamate (11 g,
50 mmol) in anhydrous tetrahydrofuran (0.10 L). After 3 h at
–50 °C, the mixture was treated with iodine (13 g, 0.10 mol) and,
at +25 °C, with a saturated aqueous solution (50 mL) of sodium
thiosulfate before being extracted with diethyl ether (3×0.10 L).
Evaporation and crystallization from hexanes gave colorless
c) tert-Butyl 2-[(E)-2-Chloroethenyl]-4-fluorophenylcarbamate: At
–25 °C, a vigorously stirred suspension of chloromethyl(triphenyl)-
1
[70]
prisms: m.p. 88–90 °C; 12.9 g (77%). H NMR: δ = 7.61 (dd, J =
phosphonium iodide
(7.8 g, 25 mmol) in tetrahydrofuran
8.0, 1.5 Hz, 1 H), 7.10 (ddd, J = 9.5, 9.5, 1.0 Hz, 1 H), 6.95 (ddd,
(0.10 L) was treated dropwise, in the course of 15 min, with tert-
butyllithium (50 mmol) in pentanes (40 mL) After further 15 min
of stirring at –25 °C, tert-butyl N-(4-fluoro-2-formylphenyl)carba-
mate (5.3 g, 25 mmol) in tetrahydrofuran (15 mL) was added. The
organic phase was absorbed on silica gel (50 mL). The powder,
when dry, was put on top of a celite pad (0.10 L). Elution with a 1:9
(v/v) mixture of ethyl acetate and hexanes followed by sublimation
J 11.0, 8.0, 5.5 Hz, 1 H), 6.0 (broad s, 1 H), 1.51 (s, 9 H) ppm. 13
C
NMR δ = 158.2 (d, J = 254 Hz), 152.8, 134.2, 129.1, 127.8, 116.3
(d, J = 21 Hz), 99.0, 81.1, 28.7 (3 C) ppm. 19F NMR: δ = –111.4
(dd, J = 14.0, 5.0 Hz) ppm. MS (c.i.): m/z (%) = 337 (7) [M+], 299
(2), 282 (10), 263 (1), 273 (100), 193 (1), 155 (8), 137 (3), 111 (48).
C11H13FINO2 (337.13): calcd. C 39.19, H 3.89; found C 39.30, H
3.98.
1
afforded colorless needles; m.p. 65–67 °C; yield: 4.47 g, (66%). H
NMR: δ = 7.13 (dd, J = 9.7, 3.2 Hz, 1 H), 6.97 (ddd, J = 9.6, 8.5,
3.6 Hz, 1 H), 6.79 (dd, J = 17.5, 11.5 Hz, 1 H), 6.3 (broad s, 1 H),
5.69 (dd, J = 12.4, 1.3 Hz, 1 H), 5.44 (dd, J = 11.0, 1.1 Hz, 1 H),
1.52 (s, 9 H) ppm. 13C NMR δ = 159.6 (d, J = 247), 153.3, 129.0,
128.5, 124.5, 118.5, 115.6, 115.2 (d, J = 23 Hz), 112.8 (d, J =
26 Hz), 77.2, 28.4 (3 C) ppm. MS (c.i.): m/z (%) = 289 (4)
[M+ +NH4], 272 (3) [M+ +H], 255 (100), 238 (72), 212 (13), 199
(82), 182 (41), 137 (28). C13H15ClFNO2 (271.72): calcd. C 57.47,
H 5.56; found C 57.11, H 5.32.
h) tert-Butyl 6-Fluoro-2-[2-(trimethylsilyl)ethynyl]phenylcarbamate:
A mixture of tert-butyl (2-iodo-6-fluorophenyl)carbamate (17 g,
50 mmol), (trimethylsilyl)acetylene (8.5 mL, 5.9 g, 60.0 mmol),
bis(triphenylphosphane)palladium dichloride (35 g, 5.0 mmol),
copper() iodide (0.9 g, 5.0 mmol) and triethylamine (50 mL) were
heated to +50 °C for 5 h. The reaction mixture was poured into a
1.0  solution (0.10 L) of citric acid, extracted with diethyl ether
(3×50 mL) and filtered through a celite pad. The combined or-
ganic layers were dried and the solvents evaporated. Crystallization
from hexanes gave colorless prisms; m.p. 102–104 °C; 11.6 g (75%).
1H NMR: δ = 7.25 (symm. m, 1 H), 7.10 (symm. m, 2 H), 6.3
(broad s, 1 H), 1.52 (s, 9 H), 0.28 (s, 9 H) ppm. 13C NMR δ =
155.4 (d, J = 250 Hz), 152.7, 128.8, 127.6 (d, J = 14 Hz), 127.1,
126.3, 116.9 (d, J = 21 Hz), 101.5, 99.9, 80.8, 28.2 (3 C), 1.2 (3 C)
ppm. 19F NMR: δ = –119.2 (t, J = 8.1 Hz) ppm. MS (c.i.): m/z (%)
= 307 (3) [M+], 252 (34), 236 (8), 207 (100), 192 (58), 176 (12), 149
(2), 130 (24), 130 (24). C16H22FNO2Si (307.44): calcd. C 62.51, H
7.21; found C 62.60, H 7.27.
d) tert-Butyl N-(2-Fluorophenyl)carbamate: Prepared from 2-fluoro-
aniline (19 mL, 22 g, 0.20 mol) analogously as tert-butyl N-(4-fluo-
rophenyl)carbamate. Crystallization from hexanes gave colorless
needles; m.p. 45–46 °C (ref.[34] m.p. 46–47 °C); yield: 35.9 g (85%).
1H NMR: δ = 8.07 (t, J = 8.0 Hz, 1 H), 7.11 (t, J = 7.9 Hz, 1 H),
7.04 (d, J = 11.2 Hz, 1 H), 6.9 (m, 1 H), 6.7 (broad s, 1 H), 1.51
(s, 9 H) ppm. 13C NMR δ = 153.2, 151.7 (d, J = 157.5), 127.3,
124.5, 123.2, 121.9, 114.7 (d, J = 12 Hz), 81.1, 28.3 (3 C) ppm. MS
(c.i.): m/z (%) = 229 (35) [M+ +NH4], 212 (43) [M+ +1], 173 (9),
156 (86), 111 (100).
Halofluoroindoles
e) tert-Butyl N-(2-Fluoro-6-formylphenyl)carbamate: Prepared,
analogously as tert-butyl N-(4-fluoro-2-formylphenyl)carbamate,
from tert-butyl N-(2-fluorophenyl)carbamate[34] (21 g, 0.10 mol).
Sublimation afforded tiny colorless prisms; m.p. 58–60 °C; yield:
7-Bromo-4-fluoroindole (17a): At –40 °C, vinylmagnesium bromide
(75 mmol) in tetrahydrofuran (75 mL) was added dropwise, in the
course of 30 min, to a solution of 1-bromo-4-fluoro-2-nitrobenzene
(see below; 5.5 g, 25 mmol) in tetrahydrofuran (100 mL). After 1 h
at –40 °C, the mixture was poured into a saturated aqueous solu-
tion (50 mL) of ammonium chloride. The organic layer was evapo-
rated; colorless needles (from pentanes); m.p. 28–29 °C; yield:
2.78 g (52%). 1H NMR: δ = 8.4 (broad s, 1 H), 7.26 (t, J = 1.4 Hz,
1 H), 7.24 (d, J = 4.1 Hz, 1 H), 6.72 (dd, J = 11.6, 6.7 Hz, 1 H),
6.71 (d, J = 1.4 Hz, 1 H) ppm. 13C NMR δ = 156.0 (d, J = 247 Hz),
137.2, 124.7 (d, J = 21 Hz), 118.2, 106.7 (d, J = 19 Hz), 100.2, 99.1,
97.8 ppm. 19F NMR: δ = –124.1 (d, J = 8.0 Hz) ppm. MS (c.i.):
m/z (%) = 215 (100) [M+ +H], 191 (10), 150 (6), 136 (33), 124 (14),
112 (19), 98 (24). C8H5BrFN (214.04): calcd. C 44.89, H 2.35;
found C 44.91, H 2.43.
1
17.2 g (72%). H NMR: δ = 10.0 (s, 1 H), 7.9 (broad s, 1 H), 7.57
(d, J = 7.9 Hz, 1 H), 7.37 (ddd, J = 9.9, 9.1, 1.8 Hz, 1 H), 7.29 (d,
J = 7.9, 4.1 Hz, 1 H), 1.51 (s, 9 H) ppm. 13C NMR δ = 191.2, 156.2
(d, J = 252 Hz), 152.7, 129.2, 127.7, 127.2, 125.3, 121.4 (d, J =
25 Hz), 81.7, 28.1 (3 C) ppm. MS (c.i.): m/z (%) = 257 (6)
[M+ +NH4], 240 (26) [M+ +1], 212 (9), 201 (100), 184 (45), 173 (9),
139 (59), 111 (23). C12H14FNO3 (239.25): calcd. C 60.24, H 5.90;
found C 60.85, H 5.81.
f) tert-Butyl 2-[(E)-2-Chloroethenyl]-6-fluorophenylcarbamate: Pre-
pared, as described above for tert-butyl 2-[(E)-2-chloroethenyl]-4-
fluorophenylcarbamate,
from
tert-butyl
N-(2-fluoro-6-for-
mylphenyl)carbamate (5.3 g, 25 mmol). Using a 1:9 (v/v) mixture
of ethyl acetate and hexanes, the product was eluted from a column
filled with silica gel (50 mL) and sublimed; colorless needles; m.p.
65–67 °C; yield: 4.47 g (66%). 1H NMR: δ = 7.0 (m, 3 H), 6.89 (d,
1-Bromo-4-fluoro-2-nitrobenzene: A mixture of 65% nitric acid
(13 mL) and 1-bromo-4-fluorobenzene (28 mL, 44 g, 0.25 mol) in
98% sulfuric acid (0.10 L) was kept 15 min at 0 °C, before being
poured onto crushed ice (0.10 kg), and extracted with dichloro-
Eur. J. Org. Chem. 2006, 2956–2969
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2965

M. Schlosser, A. Ginanneschi, F. Leroux
FULL PAPER
methane (2×50 mL). Evaporation and crystallization of the residue
from pentanes gave yellowish needles; m.p. 39–41 °C (ref.[71] 40–
41 °C); yield: 39.6 g (72%). 1H NMR: δ = 7.75 (dd, J = 8.9, 5.4 Hz,
1 H), 7.62 (dd, J = 7.8, 3.0 Hz, 1 H), 7.21 (ddd, J = 8.6, 7.0, 2.9 Hz,
1 H) ppm. 13C NMR δ = 161.5 (d, J = 252 Hz), 159.2, 136.7, 121.8
(d, J = 23 Hz), 114.1 (d, J = 25 Hz), 109.2 ppm. MS (c.i.): m/z (%)
= 219 (100) [M+ – H], 191 (8), 175 (20), 161 (34), 127 (5), 111 (19),
94 (84). C6H3BrFNO2 (220.00): calcd. C 32.76, H 1.37; found C
32.81, H 1.42.
21 Hz) ppm. MS (c.i.): m/z (%) = 219 (63) [M+ – H], 203 (9), 189
(47), 175 (8), 161 (31), 142 (2), 127 (39), 94 (100). C6H3BrFNO2
(220.00): calcd. C 32.76, H 1.37; found C 32.81, H 1.59.
5-Bromo-7-fluoroindole (20a): Prepared, analogously as 7-bromo-4-
fluoroindole (17a), from 4-bromo-2-fluoro-1-nitrobenzene (see be-
low; 5.5 g, 25 mmol); colorless needles (from pentanes); m.p. 24–
1
25 °C; yield: 1.92 g (36%). H NMR: δ = 8.4 (broad s, 1 H), 7.54
(dd, J = 1.0, 0.5 Hz, 1 H), 7.24 (t, J = 2.5 Hz, 1 H), 7.06 (dd, J =
10.6, 2.0 Hz, 1 H), 6.53 (dt, J = 2.9, 2.1 Hz, 1 H) ppm. 13C NMR
150.2, 146.5 (d, J = 237 Hz), 132.3, 124.7, 119.1, 111.7, 110.2 (d, J
= 23 Hz), 102.7 ppm. 19F NMR: δ = –112.9 (d, J = 10.2 Hz) ppm.
MS (c.i.): m/z (%) = 231 (6) [M+ +NH4], 215 (100) [M+], 189 (5),
150 (3), 134 (50), 107 (36). C8H5BrFN (214.04): calcd. C 44.89, H
2.35; found C 45.34, H 2.30.
7-Bromo-5-fluoroindole (18a): Prepared, analogously as 7-bromo-4-
fluoroindole (17a), from 2-bromo-4-fluoro-1-nitrobenzene (see be-
low; 6.6 g, 30 mmol); colorless needles (from pentanes); m.p. 27–
28 °C; yield: 3.66 g (57%). 1H NMR: δ = 8.3 (broad s, 1 H), 7.2
(m, 2 H), 7.15 (dd, J = 9.1, 2.6 Hz, 1 H), 6.56 (dd, J = 3.2, 2.4 Hz,
1 H) ppm. 13C NMR 157.5 (d, J = 240 Hz), 132.0, 129.0, 126.7,
113.0 (d, J = 28 Hz), 105.5 (d, J = 26 Hz), 104.2, 103.8 ppm. MS
(c.i.): m/z (%) = 215 (100) [M+ +1], 185 (2), 151 (2), 134 (9), 107
(24). C8H5BrFN (214.04): calcd. C 44.89, H 2.35; found C 44.91,
H 2.39.
5-Bromo-4-fluoro-1-(triisopropylsilyl)indole (21b): sec-Butyllithium
(10 mmol) in pentanes (8.0 mL) was added to a solution of 4-
fluoro-1-(triisopropylsilyl)indole (13b, 2.9 g, 10 mmol) and
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (2.1 mL, 1.7 g,
10 mmol) in tetrahydrofuran (20 mL) cooled in a dry ice/methanol
bath. After 6 h –75 °C, the mixture was treated with 1,2-dibromo-
1,1,2,2-tetrafluoroethane (2.6 g, 1.7 mL, 10 mmol) before being
evaporated. Elution with hexanes from a column filled with silica
gel (50 mL) gave a colorless liquid; m.p. –11 to –12 °C; yield: 3.11 g
2-Bromo-4-fluoro-1-nitrobenzene: Prepared, analogously as 1-
bromo-4-fluoro-2-nitrobenzene, from 3-fluoro-bromobenzene
(28 mL, 43 g, 0.25 mol); yellowish needles (from pentanes); m.p.
40–42 °C (ref.[72] 42 °C); yield: 41.8 g (76%). 1H NMR: δ = 7.99
(dd, J = 8.9, 5.1 Hz, 1 H), 7.50 (dd, J = 7.9, 3.7 Hz, 1 H), 7.22
(ddd, J = 8.9, 7.4, 2.5 Hz, 1 H) ppm. 13C NMR δ = 163.5 (d, J =
260 Hz), 145.5, 127.5, 121.5 (d, J = 26 Hz), 115.7, 115.0 (d, J =
1
(84%). H NMR: δ = 7.2 (m, 2 H), 7.04 (d, J = 8.7 Hz, 1 H), 6.71
(d, J = 3.1 Hz, 1 H), 1.66 (sept, J = 7.6 Hz, 3 H), 1.12 (d, J =
7.6 Hz, 18 H) ppm. 13C NMR 152.3 (d, J = 247 Hz), 142.3, 131.9,
29 Hz) ppm. MS (c.i.): m/z (%) = 219 (100) [M+], 205 (15), 191 124.9, 121.5 (d, J = 21 Hz), 110.7, 100.7, 97.8 (d, J = 19 Hz), 18.0
(90), 173 (32), 161 (66), 111 (18), 94 (100). C6H3BrFNO2 (220.00): (3 C), 12.7 (6 C). 19F NMR: δ = –116.4 (d, J = 6.4 Hz) ppm. MS
calcd. C 32.76, H 1.37; found C 32.88, H 1.39.
(c.i.): m/z (%) = 371 (100) [M+ +H], 327 (10), 292 (3), 247 (3), 204
(2), 130 (2). C17H25BrFNSi (370.38): calcd. C 55.13, H 6.80; found
C 56.19, H 7.21.
4-Bromo-7-fluoroindole (19a): Prepared, analogously as 7-bromo-
4-fluoroindole (17a), from 4-bromo-1-fluoro-2-nitrobenzene (11 g,
50 mmol). Upon distillation a yellowish liquid was collected; m.p.
24–25 °C; yield: 3.61 g (34%). 1H NMR (400 MHz, CDCl3): δ =
8.6 (broad s, 1 H), 7.26 (t, J = 2.9 Hz, 1 H), 7.16 (dd, J = 8.2,
3.9 Hz, 1 H), 6.78 (dd, J = 10.4, 8.3 Hz, 1 H), 6.61 (symm. m, 1
H) ppm. 13C NMR δ = 149.5 (d, J = 243 Hz), 138.2, 126.2, 123.1,
117.5, 108.2 (d, J = 19 Hz), 104.1, 98.5. 19F NMR: δ = –106.1 (t,
J = 6.8 Hz) ppm. MS (c.i.): m/z (%) = 215 (100) [M+ +H], 189 (31),
5-Bromo-4-fluoroindole (21a): Tetrabutylammonium fluoride hy-
drate (0.10 g, 2.0 mmol) was added to a solution of 5-bromo-4-
fluoro-1-(triisopropylsilyl)indole (21b, 0.37 g, 1.0 mmol) in tetra-
hydrofuran (5 mL). After 5 min at +25 °C, the reaction mixture was
diluted with diethyl ether (15 mL), washed with brine (2×5 mL),
dried and the solvents evaporated. Crystallization from hexanes
gave colorless needles; m.p. 33–34 °C; yield: 0.190 g (89%). 1H
161 (2), 134 (39), 107 (53), 90 (12). C8H5BrFN (214.04): calcd. C NMR: δ = 8.9 (broad s, 1 H), 7.35 (dd, J = 8.6, 6.9 Hz, 1 H), 7.16
44.89, H 2.35; found C 45.07, H 2.30.
(t, J = 2.8 Hz, 1 H), 7.06 (dd, J = 8.4, 1.1 Hz, 1 H), 6.61 (symm.
m, 1 H) ppm. 13C NMR 153.2 (d, J = 247 Hz), 138.2, 131.7, 129.5,
126.5, 126.1, 109.2, 99.2 (d, J = 27 Hz) ppm. 19F NMR: δ = –114.2
(d, J = 6.8 Hz) ppm. MS (c.i.): m/z (%) = 213 (80) [M+], 174 (4),
149 (15), 134 (100), 107 (84). C8H5BrFN (214.04): calcd. C 44.89,
H 2.35; found C 45.07, H 2.30.
4-Bromo-2-fluoroaniline: A suspension containing 2-fluoroaniline
(2.1 mL, 2.8 g, 25 mmol) and N-bromosuccinimide (4.4 g,
25 mmol) in chloroform (50 mL) was stirred for 2 h at +25 °C. The
meanwhile homogeneous mixture was washed with a 0.10  aque-
ous solution (2×50 mL) of sodium thiosulfate. The organic layer
was evaporated and the residue crystallized from hexanes; colorless
needles; m.p. 40–42 °C (ref.[73] 41–42 °C); yield: 3.61 g (76%). 1H
NMR: δ = 7.14 (dd, J = 10.7, 2.1 Hz, 1 H), 7.05 (ddd, J = 9.1, 0.9,
5-Chloro-4-fluoro-1-(triisopropylsilyl)indole (22b): Prepared, analo-
gously as the bromo analog 21b, from 4-fluoro-1-(triisopropylsilyl)-
indole (13b) (2.9 g, 10 mmol) using 1,1,2-trichloro-1,2,2-trifluoro-
0.4 Hz, 1 H), 6.66 (t, J = 8.9 Hz, 1 H) ppm. 13C NMR δ = 152.3 ethane (1.3 mL, 1.5 g, 10 mmol) as the reagent. The same work-up
(d, J = 242 Hz), 134.2, 127.5, 118.7 (d, J = 18 Hz), 118.2, 109.1
ppm. MS (c.i.): m/z (%) = 191 (100) [M+ +H], 170 (23), 161 (5), 152
(10), 137 (6). C6H5BrFN (190.02): calcd. C 37.93, H 2.65; found C
37.82, H 2.75.
gave again a colorless liquid; m.p. 35–36 °C; yield: 2.12 g (65%).
1H NMR: δ = 7.2 (m, 2 H), 7.09 (dd, J = 8.9, 7.1 Hz, 1 H), 6.71
(d, J = 3.1 Hz, 1 H), 1.65 (sept, J = 7.5 Hz, 3 H), 1.11 (d, J =
7.2 Hz, 18 H) ppm. 13C NMR 151.5 (d, J = 249 Hz), 141.7, 133.3,
132.1, 122.7, 121.7 (d, J = 19 Hz), 110.5, 100.5, 18.1 (3 C), 12.7 (6
C) ppm. 19F NMR: δ = –115.6 (d, J = 6.9 Hz) ppm. MS (c.i.):
m/z (%) = 326 (100) [M+ +H], 308 (3), 274 (8), 240 (5), 205 (6), 174
(11). C17H25ClFNSi (325.93): calcd. C 62.65, H 7.73; found C
62.91, H 7.72.
4-Bromo-2-fluoro-1-nitrobenzene: At +25 °C, 35% aqueous hydro-
gen peroxide (56 mL, 0.58 mol) was added to 4-bromo-2-fluoroani-
line (15 mL, 19 g, 0.10 mol) in trifluoroacetic acid (0.20 L) over a
period of 30 min. The mixture was heated to reflux for 1 h, before
being poured onto ice (90 g). The precipitate was collected as yel-
lowish platelets; m.p. 84–86 °C (ref.[74] 85–86 °C); yield: 15.8 g
5-Chloro-4-fluoroindole (22a): Prepared, analogously as the bromo
1
(72%). H NMR: δ = 7.99 (t, J = 8.3 Hz, 1 H), 7.88 (dd, J = 10.6, analog 21a, from 5-chloro-4-fluoro-1-(triisopropylsilyl)indole (22b,
2.1 Hz, 1 H), 7.49 (dt, J = 9.1, 1.9 Hz, 1 H) ppm. 13C NMR δ =
155.2 (d, J = 270 Hz), 137.2, 129.5, 128.2, 127.1, 121.5 (d, J =
0.33 g, 1.0 mmol); colorless needles (from hexanes); m.p. 22–23 °C;
1
yield: 0.149 g (88%). H NMR: δ = 8.3 (broad s, 1 H), 7.31 (t, J =
2966
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2956–2969

Rational Access to Twelve Fluoroindolecarboxylic Acids
FULL PAPER
3.1 Hz, 1 H), 7.26 (dd, J = 8.9, 3.5 Hz, 1 H), 7.05 (t, J = 8.4 Hz, 1
NMR: δ = 7.69 (d, J = 7.9 Hz, 1 H), 7.41 (d, J = 10.9 Hz, 1 H),
H), 6.66 (symm. m, 1 H) ppm. 13C NMR 153.7 (d, J = 237 Hz), 7.32 (d, J = 2.9 Hz, 1 H) 6.74 (d, J = 3.1 Hz, 1 H), 1.72 (sept, J =
135.7, 132.5, 126.7, 111.5 (d, J = 19 Hz), 110.9, 110.2, 102.1. 19F 7.6 Hz, 3 H), 1.21 (d, J = 7.9 Hz, 18 H) ppm. 13C NMR δ = 154.2
NMR: δ = –112.4 (t, J = 6.9 Hz) ppm. MS (c.i.): m/z (%) = 169
(d, J = 240 Hz), 139.2, 132.7, 128.5, 120.7, 113.2, 104.2, 101.3 (d,
(100) [M+], 151 (3), 134 (11), 115 (3), 107 (22), 91 (3). C8H5ClFN J = 28 Hz), 18.1 (3 C), 12.7 (6 C) ppm. MS (c.i.): m/z (%) = 326
(169.58): calcd. C 56.66, H 2.97; found 56.56, H 3.03.
(100) [M+], 308 (2), 282 (14), 240 (3), 212 (5). C17H25ClFNSi
(325.93): calcd. C 62.65, H 7.73; found C 62.87, H 7.90.
4-Chloro-5-fluoro-1-(triisopropylsilyl)indole (23b):
2,2,6,6-Tet-
ramethylpiperidine (1.7 mL, 1.4 g, 10 mmol), N,N,NЈ,NЈЈ,NЈЈ-
pentamethyldiethylenetriamine (2.1 mL, 1.7 g, 10 mmol) and 5-
fluoro-1-(triisopropylsilyl)indole (14a, 1.45 g, 5.0 mmol) were
added consecutively to a solution of butyllithium (10 mmol) in
tetrahydrofuran (20 mL) and hexanes (6.0 mL) cooled in a dry ice/
methanol bath. After 6 h at –75 °C, the mixture was treated with
1,1,2-trichloro-1,2,2-trifluoroethane (0.62 mL, 0.78 g, 5.0 mmol)
before it was allowed to reach +25 °C. The organic phase was ab-
sorbed on silica gel (10 mL). The powder, when dry, was put on
the top of a wet column filled with more silica (0.10 L). Elution
with hexanes gave a colorless liquid; m.p. –14 to –13 °C; yield:
1.01 g (62%). 1H NMR: δ = 7.3 (m, 2 H), 6.97 (t, J = 9.4 Hz, 1
H), 6.72 (d, J = 3.2 Hz, 1 H) 1.67 (sept, J = 7.5 Hz, 3 H), 1.12 (d,
J = 7.5 Hz, 18 H) ppm. 13C NMR 154.1 (d, J = 238 Hz), 138.2,
134.5, 131.9, 113.2, 110.8 (d, J = 31 Hz), 105.7 (d, J = 29 Hz),
103.4, 19.2 (3 C), 13.2 (6 C) ppm. 19F NMR: δ = –119.6 (m) ppm.
MS (c.i.): m/z (%) = 325 (100) [M+], 282 (76), 248 (58), 206 (34), 178
(34), 157 (28), 130 (79), 102 (31). C17H25ClFNSi (325.92): calcd. C
62.65, H 7.73; found C 62.97, H 7.67.
5-Bromo-6-fluoro-1-(triisopropylsilyl)indole (26b): Prepared, analo-
gously as the isomer 21b, from 6-fluoro-1-(triisopropylsilyl)indole
(15b, 2.9 g, 10 mmol); colorless liquid; m.p. –14 to –13 °C; yield:
1
3.11 g (84%). H NMR: δ = 7.75 (d, J = 7.1 Hz, 1 H), 7.29 (d, J
= 10.6 Hz, 1 H), 7.23 (d, J = 3.1 Hz, 1 H), 6.54 (d, J = 3.2 Hz, 1
H), 1.66 (sept, J = 7.4 Hz, 3 H), 1.14 (d, J = 7.4 Hz, 18 H) ppm.
13C NMR 155.1 (d, J = 237 Hz), 139.7, 132.5, 129.3, 123.7, 104.2,
101.2 (d, J = 27 Hz), 100.7, 17.3 (3 C), 12.5 (6 C) ppm. 19F NMR:
δ = –116.3 (dd, J = 10.4, 7.0 Hz) ppm. MS (c.i.): m/z (%) = 396
(7), 371 (1) [M+ +H], 328 (24), 291 (18), 248 (100), 206 (45), 178
(54). C17H25BrFNSi (370.38): calcd. C 55.13, H 6.80; found C
55.84, H 6.86.
6-Fluoro-5-iodo-1-(triisopropylsilyl)indole (27b): Prepared, analo-
gously as 5-bromo-4-fluoro-1-(triisopropylsilyl)indole (21b), from
6-fluoro-1-(triisopropylsilyl)indole (15b, 2.9 g, 10 mmol) using ele-
mental iodine (1.3 g, 10 mmol) as the reagent. The product was
eluted with hexanes from a silica gel column as a colorless liquid;
1
m.p. –8 to –7 °C; yield: 3.14 g (75%). H NMR: δ = 7.95 (d, J =
6.6 Hz, 1 H), 7.27 (s, 1 H), 7.21 (d, J = 3.2 Hz, 1 H), 6.52 (d, J =
2.9 Hz, 1 H), 1.65 (sept, J = 7.4 Hz, 3 H), 1.21 (d, J = 7.4 Hz, 18
H) ppm. 13C NMR 157.5 (d, J = 235 Hz), 140.5, 132.3, 129.9,
104.1, 100.5 (d, J = 31 Hz), 85.1, 72.0 (d, J = 29 Hz), 18.5 (3 C),
13.1 (6 C) ppm. 19F NMR: δ = –128.1 (d, J = 9.1 Hz) ppm. MS
4-Chloro-5-fluoroindole (23a): Prepared, analogously as the bromo-
fluoroindole 21a, from 5-chloro-4-fluoro-1-(triisopropylsilyl)indole
(23b, 0.33 g, 1.0 mmol); colorless needles (from hexanes); m.p. 21–
1
22 °C; yield: 0.160 g (94%). H NMR: δ = 8.3 (broad s, 1 H), 7.29
(t, J = 3.8 Hz, 1 H), 7.24 (dd, J = 8.7, 3.6 Hz, 1 H), 7.01 (t, J = (c.i.): m/z (%) = 417 (100) [M+], 374 (24), 346 (2), 291 (8), 248 (9),
8.4 Hz, 1 H), 6.66 (symm. m, 1 H) ppm. 13C NMR 153.7 (d, J = 204 (13), 130 (16). C17H25FINSi (417.45): calcd. C 48.92, H 6.04;
237 Hz), 147.7, 132.7, 126.1, 111.5 (d, J = 26 Hz), 110.7, 109.7,
101.5 ppm. 19F NMR: δ = –112.6 (t, J = 7.0 Hz) ppm. MS (c.i.):
m/z (%) = 169 (93) [M+], 160 (11), 134 (14), 107 (23), 84 (100).
C8H5ClFN (169.58): calcd. C 56.66, H 2.97; found C 56.76, H 3.05.
found C 49.20, H 6.21.
6-Fluoro-5-iodoindole (27a): Prepared, analogously as 5-bromo-4-
fluoroindole (21a), from 6-fluoro-5-iodo-1-(triisopropylsilyl)indole
(27b, 1.2 g, 3.0 mmol); colorless cubes (from hexanes); m.p. 37–
1
4,6-Dichloro-5-fluoro-1-(triisopropylsilyl)indole (24b): Prepared,
analogously as 5-chloro-4-fluoro-1-(triisopropylsilyl)indole (22b),
from 4-chloro-5-fluoro-1-(triisopropylsilyl)indole (23b, 3.25 g,
39 °C; yield: 0.412 g (79%). H NMR: δ = 8.2 (broad s, 1 H), 7.35
(dd, J = 8.9, 2.1 Hz, 1 H), 7.27 (symm. m, 2 H), 6.65 (dd, J = 3.1,
2.2 Hz, 1 H) ppm. 13C NMR 158.0 (d, J = 240 Hz), 135.0, 128.1,
10 mmol); colorless oil; m.p. –5 to –4 °C; yield: 2.71 g (75%). 1H 126.5, 119.2 (d, J = 27 Hz), 106.7 (d, J = 29 Hz), 104.5, 72.2 ppm.
NMR: δ = 7.39 (d, J = 5.4 Hz, 1 H), 7.30 (d, J = 3.2 Hz, 1 H),
6.69 (d, J = 3.1 Hz, 1 H), 1.66 (sept, J = 7.9 Hz, 3 H), 1.14 (d, J
19F NMR*: δ = –104.4 (t-like dd, J = 7.0, 9.0 Hz) ppm. MS (c.i.):
m/z (%) = 278 (9) [M+ +NH4], 262 (100) [M+ +H], 238 (3), 161
= 7.7 Hz, 18 H) ppm. 13C NMR 149.1 (d, J = 240 Hz), 136.7, (14), 134 (17), 107 (11), 81 (3). C8H5FIN (261.03): calcd. C 36.81,
133.7, 129.7, 115.5 (d, J = 21 Hz), 113.1, 105.5 (d, J = 23 Hz),
103.7, 18.5 (3 C), 13.1 (6 C) ppm. 19F NMR*: δ = –131.0 (d, J =
4.9 Hz) ppm. MS (c.i.): m/z (%) = 360 (100) [M+], 316 (29), 292 (6),
248 (20), 174 (16), 157 (30), 130 (36). C17H24Cl2FNSi (360.37):
calcd. C 56.66, H 6.71; found C 57.88, H 6.74.
H 1.93; found C 36.82, H 1.95.
4-Bromo-6-fluoro-1-(triisopropylsilyl)indole
(29b):
2,2,6,6-Tet-
ramethylpiperidine (0.34 mL, 0.28 g, 2.0 mmol), N,N,NЈ,NЈЈ,NЈЈ-
pentamethyldiethylenetriamine (0.42 mL, 0.35 g, 2.0 mmol) and 5-
bromo-6-fluoro-1-(triisopropylsilyl)indole (26b, 0.74 g, 2.0 mmol)
were added consecutively to a solution of butyllithium (2.0 mmol)
4,6-Dichloro-5-fluoroindole (24a): Prepared, analogously as the bro-
mofluoroindole 21a, from 4,6-dichloro-5-fluoro-1-(triisopropylsi- in tetrahydrofuran (5.0 mL) and hexanes (2.0 mL) cooled in a dry
lyl)indole (24b, 0.71 g, 2.0 mmol); colorless needles; m.p. 89–91 °C;
ice/methanol bath. After 6 h at –75 °C, the mixture was treated
with water (5.0 mL). The organic phase was washed with brine
0.391 g (96%). 1H NMR: δ = 8.3 (broad s, 1 H), 7.36 (d, J = 5.5 Hz,
1 H), 7.29 (t, J = 2.5 Hz, 1 H), 6.64 (d, J = 2.2 Hz, 1 H) ppm. 13C (3×10 mL), dried and the solvents evaporated. NMR analysis of
NMR 149.6 (d, J = 239 Hz), 131.4, 127.1, 126.4, 117.1 (d, J =
25 Hz), 112.3, 111.2, 102.1 ppm. 19F NMR*: δ = –131.2 (d, J =
5.9 Hz) ppm. MS (c.i.): m/z (%) = 203 (100) [M+ – 1], 168 (16), 141
the reaction mixture using dioxane as an internal standard, re-
vealed a 5:1 ratio between the 4- and 5-bromo-6-fluoro-1-(triiso-
propylsilyl)indoles (29b and 26b); yield: 0.585 g (79%). 1H NMR*:
(28), 105 (9), 91 (3). C8H4Cl2FN (204.03): calcd. C 47.09, H 1.98; δ = 7.62 (dd, J = 8.6, 5.8 Hz, 1 H), 7.31 (d, J = 3.3 Hz, 1 H), 6.99
found C 47.00, H 1.85.
(dt, J = 9.3, 2.2 Hz, 1 H), 6.69 (dt, J = 19.8, 3.3 Hz, 1 H), 1.75
(sept, J = 7.5 Hz, 3 H), 1.24 (d, J = 7.6 Hz, 18 H) ppm. MS (c.i.):
m/z (%) = 371 (100) [M+], 328 (70), 247 (77), 205 (28).
5-Chloro-6-fluoro-1-(triisopropylsilyl)indole (25b): Prepared, analo-
gously as 5-chloro-4-fluoro-1-(triisopropylsilyl)indole (22b), from
6-fluoro-1-(triisopropylsilyl)indole (15b, 2.9 g, 10 mmol); colorless
cubes (from hexanes); m.p. 55–56 °C; yield: 2.77 g (85%). 1H
6-Fluoro-4-iodoindole
(30a):
2,2,6,6-Tetramethylpiperidine
(0.34 mL, 0.28 g, 2.0 mmol), N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethyl-
Eur. J. Org. Chem. 2006, 2956–2969
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2967

M. Schlosser, A. Ginanneschi, F. Leroux
FULL PAPER
enetriamine (0.42 mL, 0.35 g, 2.0 mmol) and 6-fluoro-5-iodo-1-(tri-
1 H), 1.71 (sept, J = 7.5 Hz, 3 H), 1.16 (d, J = 7.9 Hz, 18 H) ppm.
13C NMR 170.7, 152.2 (d, J = 247 Hz), 140.2, 135.5, 124.7 (d, J =
isopropylsilyl)indole (27b, 0.81 g, 2.0 mmol) were added consecu-
tively to a solution of butyllithium (2.0 mmol) in tetrahydrofuran 21 Hz), 120.5, 114.5, 111.7, 101.5, 18.1 (3 C), 12.7 (6 C) ppm. 19F
(5.0 mL) and hexanes (2.0 mL) cooled in a dry ice/methanol bath.
After 6 h at –75 °C, the mixture was treated with water (5.0 mL).
The organic phase was washed with brine (3×10 mL), dried and
the solvents were evaporated. The residue was treated at 25 °C with
tetrabutylammonium fluoride hydrate (0.20 g, 4.0 mmol) in tetra-
hydrofuran (10 mL). After 5 min at 25 °C, the reaction mixture was
diluted with diethyl ether (5.0 mL), washed with brine (2×5 mL),
dried, and the solvents evaporated. The product was eluted from a
column filled with silica using a 1:9 (v/v) mixture of ethyl acetate
and hexanes; colorless cubes (from hexanes); m.p. 69–70 °C; yield:
0.460 g (88%). 1H NMR*: δ = 8.2 (broad s, 1 H), 7.97 (d, J =
5.9 Hz, 1 H), 7.17 (t, J = 2.9 Hz, 1 H), 7.11 (d, J = 8.9 Hz, 1 H),
6.46 (symm. m, 1 H) ppm. 13C NMR 157.7 (d, J = 238 Hz), 135.7,
130.8, 127.2, 125.5, 102.1, 98.2 (d, J = 29 Hz), 71.2 (d, J = 32 Hz)
ppm. 19F NMR*: δ = –123.2 (t, J = 9.9 Hz) ppm. MS (c.i.): m/z (%)
NMR*: δ = –124.9 (d, J = 5.1 Hz) ppm. MS (c.i.): m/z (%) = 370
(100) [M+ +1], 326 (41), 231 (26), 214 (36), 196 (65), 168 (15), 148
(23), 134 (17), 102 (6). C18H25ClFNO2Si (369.94): calcd. C 58.44,
H 6.81; found C 58.70, H 6.84.
5-Chloro-4-fluoroindole-6-carboxylic Acid (31a): Prepared, analo-
gously as acid 28a, from 5-chloro-4-fluoro-1-(triisopropylsilyl)in-
dole-6-carboxylic acid (31b, 1.85 g, 5.0 mmol); colorless prisms
(from hexanes); m.p. Ͼ250 °C; yield: 0.84 g (79%). 1H NMR*: δ =
8.05 (t, J = 0.9 Hz, 1 H), 7.69 (t, J = 2.7, 1 H), 6.69 (symm. m, 1
H) ppm. 13C NMR 168.7, 152.7 (d, J = 245 Hz), 147.7, 138.1,
131.2, 125.7, 121.7 (d, J = 24 Hz), 113.2, 99.1 ppm. 19F NMR*: δ
= –122.6 (d, J = 4.9 Hz) ppm. MS (c.i.): m/z (%) = 213 (19) [M+],
186 (7), 153 (4), 133 (4), 107 (3). C9H5ClFNO2 (213.59): calcd. C
50.61, H 2.36; found C 50.89, H 2.44.
= 261 (100) [M+], 135 (2), 107 (3). C8H5FIN (261.03): calcd. C 4-Chloro-5-fluoro-1-(triisopropylsilyl)indole-6-carboxylic Acid (32b):
36.81, H 1.93; found C 36.61, H 2.05.
Prepared from 4-chloro-5-fluoro-1-(triisopropylsilyl)indole (23b)
(1.3 g, 10 mmol) as described for (28b); m.p. 177–179 °C; yield:
2.66 g (72%). H NMR: δ = 8.19 (d, J = 4.9 Hz, 1 H), 7.51 (d, J
Chlorofluoroindolecarboxylic Acids
1
5-Chloro-6-fluoro-1-(triisopropylsilyl)indole-4-carboxylic Acid (28b):
= 3.1 Hz, 1 H), 6.79 (d, J = 3.5 Hz, 1 H), 1.73 (sept, J = 7.9 Hz, 3
H), 1.15 (d, J = 7.9 Hz, 18 H) ppm. 13C NMR 170.2, 152.5 (d, J
= 255 Hz), 137.5, 136.1, 135.5, 116.7, 112.3 (d, J = 22 Hz), 111.2,
104.2, 18.1 (3 C), 12.5 (6 C) ppm. 19F NMR*: δ = –127.8 (d, J =
4.9 Hz) ppm. MS (c.i.): m/z (%) = 378 (0) [M+ +NH4], 360 (100)
[M+], 326 (20), 292 (8), 256 (3), 231 (15), 170 (13), 148 (48), 130
(24). C18H25ClFNO2Si (369.94): calcd. C 58.44, H 6.81; found C
56.44, H 6.62.
2,2,6,6-Tetramethylpiperidine
(3.4 mL,
2.8 g,
20 mmol),
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (4.2 mL, 3.4 g,
20 mmol) and 5-chloro-6-fluoro-1-(triisopropylsilyl)indole (25b,
3.2 g, 10 mmol) were added consecutively to a solution of butyllith-
ium (20 mmol) in tetrahydrofuran (40 mL) and hexanes (13 mL)
cooled in a dry ice/methanol bath. After 2 h at –75 °C, the mixture
was poured onto an excess of freshly crushed dry ice. Water was
added (10 mL), the aqueous phase decanted and washed with di-
ethyl ether (3×10 mL). The combined organic layers were washed
with 1.0  solution of citric acid (2×15 mL) and brine (2×10 mL),
dried, filtered and the solvents evaporated. Crystallization from
hexanes gave colorless prisms; m.p. 181–183 °C; yield: 2.93 g
(79%). 1H NMR: δ = 7.48 (d, J = 10.3 Hz, 1 H), 7.38 (d, J =
3.0 Hz, 1 H), 7.02 (d, J = 3.6 Hz, 1 H), 1.69 (sept, J = 7.9 Hz, 3
H), 1.15 (d, J = 7.1 Hz, 18 H) ppm. 13C NMR 172.2, 154.3 (d, J
= 237 Hz), 139.1, 134.2, 128.4, 120.8, 109.2, 105.4, 104.3 (d, J =
27 Hz), 17.6 (3 C), 12.5 (6 C) ppm. 19F NMR*: δ = –121.8 (d, J =
14.9 Hz) ppm. MS (c.i.): m/z (%) = 370 (39) [M+ +H], 330 (23), 274
(28), 231 (10), 192 (8), 174 (24), 148 (93), 117 (22), 93 (11), 76 (100).
C18H25ClFNO2Si (369.94): calcd. C 58.44, H 6.81; found C 57.65,
H 6.61.
4-Chloro-5-fluoroindole-6-carboxylic Acid (32a): Prepared, analo-
gously as acid 28a, from 4-chloro-5-fluoro-1-(triisopropylsilyl)in-
dole-6-carboxylic acid (32b, 1.8 g, 5.0 mmol); colorless needles
(from 90% aqueous methanol); m.p. 213-214 °C; yield: 0.748 g
(70%). 1H NMR*: δ = 8.12 (d, J = 5.1 Hz, 1 H), 7.74 (t, J = 2.9 Hz,
1 H), 6.65 (t, J = 2.6 Hz, 1 H) ppm. 13C NMR*: 167.2, 154.2 (d,
J = 248 Hz), 133.8, 133.1, 118.1, 115.1, 112.7 (d, J = 21 Hz), 102.2,
101.2. 19F NMR*: δ = –125.6 (d, J = 4.9 Hz) ppm. MS (c.i.):
m/z (%) = 231 (100) [M+ +NH4], 213 (75) [M+], 196 (27), 186 (13),
150 (6), 107 (3). C9H5ClFNO2 (213.59): calcd. C 50.61, H 2.36;
found C 50.82, H 2.58.
Acknowledgments
5-Chloro-6-fluoroindole-4-carboxylic Acid (28a): A solution con-
taining tetrabutylammonium fluoride hydrate (1.3 g, 5.0 mmol) and
5-chloro-6-fluoro-1-(triisopropylsilyl)indole-4-carboxylic acid (28b,
1.8 g, 5.0 mmol) in tetrahydrofuran (10 mL) was kept 5 min at
25 °C, before being diluted with diethyl ether (10 mL), washed with
brine (2×10 mL), dried and the solvents evaporated. Crystalli-
zation from 90% aqueous methanol afforded colorless platelets;
m.p. 202–203 °C; yield: 0.886 g (83%). 1H NMR*: δ = 7.56 (d, J =
9.5 Hz, 1 H), 7.52 (t, J = 2.9 Hz, 1 H), 6.72 (symm. m, 1 H) ppm.
13C NMR*: 171.1, 166.2, 154.2 (d, J = 237 Hz), 134.5, 128.2, 124.2,
112.2, 102.2, 101.1 (d, J = 29 Hz) ppm. 19F NMR*: δ = –121.8 (d,
J = 10.6 Hz) ppm. MS (c.i.): m/z (%) = 231 (100) [M+ +NH4], 213
(32), 196 (7), 174 (9), 150 (6), 118 (6). C9H5ClFNO2 (213.59): calcd.
C 50.61, H 2.36; found C 50.82, H 2.58.
This work was financially supported by the Schweizerische Nation-
alfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grants 20-55Ј303-98, 20-63Ј584.00 and 20-100Ј336-02), the Bun-
desamt für Bildung und Wissenschaft, Bern (grant 97.0083 linked
to the TMR project FMRXCT-970129) and Hoffmann-La Roche,
Basel.
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1H NMR: δ = 8.21 (s, 1 H), 7.44 (d, J = 3.4, 1 H), 6.79 (d, J = 3.5,
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Eur. J. Org. Chem. 2006, 2956–2969

Rational Access to Twelve Fluoroindolecarboxylic Acids
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Received: February 10, 2006
Published Online: April 21, 2006
Eur. J. Org. Chem. 2006, 2956–2969
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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