Synthesis and derivatization of 3-perfluoroalkyl-substituted 7-azaindoles

Article abstract of DOI:10.1055/s-2006-958935

An expedient large-scale synthesis of 3-perfluoroalkyl-7-azaindoles starting from 2-fluoropyridine is presented. The activation as 6-chloro-4-nitro derivative allows the further derivatization by nucleophilic aromatic substitution in the 4-position. Georg

Full text of DOI:10.1055/s-2006-958935

PAPER
251
Synthesis and Derivatization of 3-Perfluoroalkyl-Substituted 7-Azaindoles
3
-Perfluoroalkyl-S
a
ubstituted 7
r
-
Azaind
t
oles mut Schirok,* Santiago Figueroa-Pérez, Michael Thutewohl,1 Holger Paulsen, Walter Kroh, Dagmar Klewer
Bayer HealthCare AG, Pharma Research, 42096 Wuppertal, Germany
Fax +49(202)364624; E-mail: hartmut.schirok@bayerhealthcare.com
Received 10 August 2006; revised 27 September 2006
Dedicated to Professor Barry M. Trost on the occasion of his 65th birthday
or Burgess’ reagent failed as well. The styrene 3 might be
accessible using other methods described in the litera-
ture.9 However, we altered our retrosynthetic approach,
but kept the approved ortho-lithiation and the intramolec-
ular nucleophilic substitution as ring-forming step. It was
envisaged to introduce a trifluoroacetyl moiety with a tri-
fluoroacetic acid ester as electrophile. Nitromethane
should then be a suitable C1-entity, which could be intro-
duced in a Henry reaction and which would contain the
desired nitrogen for a subsequent amino alcohol forma-
tion (Scheme 2, pathway B).
Abstract: An expedient large-scale synthesis of 3-perfluoroalkyl-
7-azaindoles starting from 2-fluoropyridine is presented. The acti-
vation as 6-chloro-4-nitro derivative allows the further derivatiza-
tion by nucleophilic aromatic substitution in the 4-position.
Key words: 7-azaindoles, cyclizations, multicomponent reactions,
directed ortho metalation, fluorine
Though rare in nature and only appearing as submoieties
in a small number of alkaloids, 7-azaindoles (1H-pyrro-
lo[2,3-b]pyridines) attract rising interest especially in me-
dicinal chemistry, wherein they serve as bioisosteres of
indole or purine ring systems. Also fluorinated com-
pounds play a major role in drug discovery2 and crop pro-
tection,3 where they are synthesized on a routine basis.
The bioisosteric replacement of hydrogen by fluorine
modulates electronic, lipophilic and conformational pa-
rameters of the structure, and a higher resistance towards
degradation by blocking metabolically labile sites is often
observed. As the facile introduction of fluorine(s) into
heterocyclic rings and their side-chains is still limited, the
development of new practical methods for their construc-
tion remains a formidable task.4
R
R
OH
HN
R'NH2
O
R'
Y
N
X
Y
N
X
X = Cl
Y = H or Cl
R
R
OH
N
N
Y
N
Y
N
In the course of one of our projects, we required multi-
gram amounts of 3-trifluoromethyl-7-azaindole (8b in
Scheme 2), which has not been described so far.5 Recent-
ly, we reported on a very reliable new access to 7-azain-
doles based on the domino epoxide opening, nucleophilic
aromatic substitution, and dehydration sequence depicted
in Scheme 1.6 To obtain the corresponding 3-trifluoro-
methyl-substituted azaindole (R = CF3), we planned to
synthesize the required epoxide 4 following our three-step
protocol starting from 2,6-dichloropyridine (Scheme 2,
pathway A). Applying Quéguiner’s7 and Schlosser’s8
ortho-metalation technique with lithiumdiisopropyl
amide to pyridine 1, and reacting the lithiated pyridine
with trifluoroacetone afforded the tertiary alcohol 2 in
73% yield. However, the elimination of the alcohol 2 to
the styrene 3 failed under various conditions. In a 3:1 mix-
ture of acetic and sulfuric acid at reflux temperature – con-
ditions which normally yield the styrenes within 30
minutes6 – the trifluoromethyl-substituted alcohol 2 was
left unchanged even after heating for 14 hours. Other re-
agents such as thionyl chloride, thionyl chloride/pyridine,
R'
R'
Scheme 1 7-Azaindole synthesis via domino epoxide opening, cy-
clization by nucleophilic aromatic substitution, and dehydration.
Originally, we began the synthesis with 2,6-dichloropyri-
dine (1a in Scheme 2). Later on we found it advantageous
to use 2-fluoropyridine (1b) as the starting material. The
addition of trifluoroacetic acid ethyl ester to the lithiated
pyridines and aqueous work-up yielded the hydrates 5a
and 5b instead of the acetyl compounds, consistent with
reports which describe the formation of stable gem-diols
of 3-trifluoroacetylpyridine.10 The dehydration can be
achieved by azeotropic distillation with toluene.11 How-
ever, we found that this step was dispensable in our syn-
thesis, since the subsequent Henry reaction in
nitromethane with 3% potassium carbonate yielded very
smoothly the desired nitro compounds 6a and 6b. Similar
reactions are known for hydrates of aldehydes.12 Recent-
ly, the Henry-type reaction of nitromethane with the hy-
drate of trifluoropyruvamides has been published.13 To
the best of our knowledge, we report here the first exam-
ple of an analogous reaction with the hydrate of an aryl ke-
tone.
SYNTHESIS 2007, No. 2, pp 0251–0258
x
x
.
x
x
.2
0
0
6
Advanced online publication: 12.12.2006
DOI: 10.1055/s-2006-958935; Art ID: T12406SS
© Georg Thieme Verlag Stuttgart · New York

252
H. Schirok et al.
PAPER
ring. Reduction conditions like stannous chloride or zinc
and calcium chloride in ethanol failed. When we used pal-
ladium on charcoal as a catalyst, the result was also not
optimal. Palladium on charcoal poisoned with zinc bro-
mide, which has been reported recently for the selective
reduction of halogen-substituted nitroarenes,15 was not
active enough to accomplish the desired transformation.
However, the reaction was successfully performed in eth-
anol under the catalysis of Raney-nickel.16 After the con-
sumption of the theoretical volume of hydrogen, the
catalyst was removed by filtration, and the ethanolic fil-
trate was heated to reflux to achieve the cyclization lead-
ing to dihydroazaindoles 7a and 7b in 77% and 81% yield,
respectively (Scheme 2). Finally, we found that the use of
platinum(IV) oxide as heterogenous precatalyst for the re-
duction of the fluoropyridine 6b resulted in a slightly low-
er yield of dihydroazaindole 7b (Scheme 3), but was
much easier to handle. Again, the isolation of the product
was very simple, since the trituration with dichloro-
methane gave already 67% of the target compound. Chro-
matography of the residue afforded additionally 6% yield.
CF3
Cl
HO CF3
a
Y
N
X
Pathway A Cl
N
Cl
Cl
N
1a: X, Y = Cl
1b: X = F, Y = H
2, 73%
3
b
Pathway B
CF3
F3C OH
OH
O
Y
N
X
Cl
N
Cl
5a: X, Y = Cl, 22%
4
5b: X = F, Y = H, 59%
c
F3C OH
F3C
CF3
OH
d
e
NO2
N
N
Y
N
X
Y
N
Y
N
RF
H
H
RF
OH
OH
6a: X, Y = Cl, 94%
6b: X = F, Y = H, 75%
7a: Y = Cl, 77%
7b: Y = H, 81%
8a: Y = Cl, 82%
8b: Y = H, 83%
a
b
NO2
N
N
F
N
N
F
H
Scheme 2 Strategies
towards
3-trifluoromethyl-7-azaindole.
Reagents and conditions: a) LDA, THF, –75 °C, then CF3COMe; b)
LDA, THF, –75 °C, then CF3CO2Et; c) MeNO2, K2CO3 (cat.), r.t.; d)
H2, Raney-Ni (cat.), EtOH, r.t.; filtration, then reflux; e) SOCl2, pyri-
dine, CH2Cl2, r.t.
c
1b
6b: RF = CF3: 92%
6c: RF = C2F5: 88%
6d: RF = C3F7: 95%
7b: RF = CF3: 73%
7c: RF = C2F5: 75%
7d: RF = C3F7: 75%
RF
We must warn the reader not to try to reproduce our
original procedure yielding compounds 6 with nitro-
methane as solvent, since our subsequent examinations re-
vealed that an exothermic decomposition takes place
above 95 °C with the release of >4900 kJ/kg (for compar-
ison: trinitrotoluene 3700 kJ/kg).14 We therefore were
forced to look for alternative reaction conditions and
found that with two equivalents of nitromethane in THF
as solvent and with potassium carbonate as catalyst the
desired compound was formed very smoothly, but without
the dangerous exothermic potential. In consequence, we
attempted to run the sequence by subsequent addition of
nitromethane to the reaction mixture without isolating the
intermediate hydrate 5. This worked very well, and the
one-pot procedure gave us access to the nitroalcohols 6a
in 74% (see experimental section) and 6b in 92% yield
(Scheme 3). Since the Henry reaction was reversible un-
der basic conditions, it turned out to be crucial to quench
the reaction by pouring the mixture into an acidic aqueous
phase. Neither chromatography nor recrystallization of
the product was necessary when we started with the fluo-
ropyridine. It proved to be sufficient to triturate the crude
product with petroleum ether, and the pure nitro com-
pound 6b was isolated by suction filtration on a 300-gram
scale.
N
N
H
8b: RF = CF3: 83%
8c: RF = C2F5: 81%
8d: RF = C3F7: 85%
Scheme
3
Synthesis of 3-perfluoroalkyl-7-azaindoles 8b–d.
Reagents and conditions: a) LDA, THF, –75 °C, then CF3CO2Et for
6b, CF3CF2CO2Me for 6c, or CF3CF2CF2CO2Et for 6d, respectively,
then MeNO2, r.t.; b) H2, PtO2 (cat.), EtOH, r.t.; filtration, then reflux;
c) SOCl2, pyridine, CH2Cl2, r.t.
The last step of the sequence consisted in the dehydration
of 7 to the aromatic system. It appeared that due to the
electron-withdrawing effect of the trifluoromethyl group
the alcohol was very stable. Whilst analogous compounds
aromatize very smoothly under acid catalysis,17 the deriv-
atives 7a and 7b did not react, and even after heating in tri-
fluoroacetic acid overnight only traces of the desired
azaindole could be detected by LC-MS. To our delight,
the reaction proceeded very smoothly with pyridine and
thionyl chloride in dichloromethane18 to afford the desired
products 8a and 8b in over 80% yield (Scheme 2). Again,
no chromatography was necessary.
Encouraged by these results we questioned if our strategy
could be of general value for the formation of 3-perfluo-
roalkylated 7-azaindoles. We therefore used methyl pen-
tafluoropropionate and ethyl heptafluorobutyrate in the
In the next step, the nitro group had to be reduced to the
amine without expelling the halogen from the pyridine
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

PAPER
3-Perfluoroalkyl-Substituted 7-Azaindoles
253
synthesis, and isolated the pentafluoroethyl and hepta- as side reaction, which is counterproductive in case of the
fluoropropyl-substituted azaindoles 8c and 8d with com- trifluoromethyl derivative, since this group is incompati-
parable overall yields as for 8b (Scheme 3).
ble with a basic hydrolysis to remove the acyl residue.23
Less N-acylation was observed when we used trichloro-
acetic acid chloride as halogen source (Scheme 4). Only a
small amount of byproduct was formed, the trichloroace-
tic acid amide of HMDS. This was not separated from the
desired compound 11. Due to the lability of the trifluoro
moiety in a basic environment, the building block 11 had
to be N-protected prior to the reaction with nucleophiles.
The SEM protecting group seemed to meet our demands.
Despite its lability against base, the azaindole 11 could be
reacted by pre-mixing it with SEM chloride and subse-
quent addition of sodium hydride. The yield of 12 was
about 90% on a 1-mmol scale. However, it dropped to
65% on 500-mmol scale and required the chromatograph-
ic purification of the product.
The 3-trifluoromethyl-7-azaindole (8b) was used as
building block in one of our projects in drug research,
wherein we needed the carbon- and oxygen-tethered bi-
arylic compounds 13 and 15 (Scheme 4). We already dis-
closed in a previous publication, that 4,6-dichloro- or 6-
chloro-4-nitro-7-azaindoles undergo nucleophilic aromat-
ic substitution in 4-position, and that the activating 6-
chloro atom may be smoothly removed by catalytic hy-
drogenation.19 Following this pathway, the activation of
3-trifluoromethyl-7-azaindole (8b) comprises its oxida-
tion, nitration, and chlorination. The N-1 protection with
the SEM-group avoids by-products resulting from N-1
deprotonation under the basic conditions of the nucleo-
philic substitution reaction.
For the target compound 13 we required 2,6-difluoro-4-
aminophenol, which can be synthesized very easily from
2,6-difluorophenol by nitration and subsequent reduction
in high yield.24 Its reaction in the phenol ether forming
step gave best results when dimethyl sulfoxide was used
as solvent and potassium carbonate as base. On a 200-
mmol scale we obtained the desired aryl ether 13 in 78%
yield.
In the N-oxidation of 8b we obtained best results using m-
chloroperbenzoic acid as oxidant.20 It turned out that the
N-oxide precipitates from the reaction mixture when the
oxidation is done in ethyl acetate as solvent. The pure
product 9 was collected simply by suction filtration in
79% yield on a 150-gram scale.
The nitration of compound 9 was done with 65% nitric ac-
id, which was added to a solution of the azaindole N-oxide
in trifluoroacetic acid at 70 °C. The nitration may also be
done at room temperature with fuming nitric acid. Analo-
gous azaindoles without a substituent in the 3-position are
nitrated preferably in the 3-position, and mixtures of the
3- and 4-nitroazaindoles are obtained.20,21 With the tri-
fluoromethyl analogue 9, the desired compound 10 was
collected by suction filtration in 76% yield.
To access the analogous methylene tethered derivative 15,
we used a suitable p-nitrophenylacetic acid ester as carbon
nucleophile. The benzyl ester was considered to meet our
demands best. It was prepared by standard procedures
from 3,4-difluoronitrobenzene and benzyl tert-butyl mal-
onate (89% yield) and subsequent decarboxylation in tri-
fluoroacetic acid (quant, see experimental section). The
nucleophilic aromatic substitution towards compound 14
proceeded smoothly in almost quantitative yield. The last
step, which comprises four simultaneous transformations
in one procedure, the nitro group reduction, the reductive
dechlorination and the reductive debenzylation and de-
carboxylation, worked in 99% yield.
For the ortho chlorination of pyridine N-oxides several
acid chlorides have been described in the literature, most
prominently phosphorous oxychloride.22 With analogous
7-azaindoles, we observed best results using methyl chlo-
roformate in the presence of hexamethyldisilazane as
base. However, the acylation of the indole nitrogen occurs
CF3
CF3
CF3
CF3
a
b
c
d
HN
–O
HN
–O
HN
SEMN
NO2
NO2
NO2
8b
quant.
79%
76%
90% (1-mmol scale)
N+
N+
10
N
N
65% (500-mmol scale)
Cl
11
Cl
9
12
CF3
CF3
CF3
CO2Bn
F
g
f
e
SEMN
SEMN
SEMN
O
F
99%
99%
78%
N
N
N
NH2
NO2
NH2
F
F
Cl
Cl
15
14
13
Scheme 4 Derivatization of 3-trifluoromethyl-7-azaindole (8b). Reagents and conditions: a) MCPBA, EtOAc, 0 °C; b) 65% HNO3,
CF3CO2H, 70 °C; c) CCl3COCl, HMDS, THF, 0 °C → r.t.; d) SEMCl, NaH, DMF; e) 4-amino-2,6-difluorophenol, K2CO3, DMSO, 120 °C; f)
benzyl (2-fluoro-4-nitrophenyl)acetate, NaH, DMF, 130 °C; g) H2, Et3N, Pd/C, r.t.
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

254
H. Schirok et al.
PAPER
reaction was warmed to r.t. and quenched with brine (100 mL). The
organic phase was separated, and the aqueous phase was extracted
with EtOAc (2 × 40 mL). The combined organic layers were dried
(Na2SO4), and the solvent was cautiously removed in vacuo. The
obtained residue (2.85 g, 89% pure, 59% yield) was used without
purification. An analytical probe was purified by sublimation
(90 °C bath temperature at 20 Torr) to yield a white solid.
In conclusion, we have discovered a highly efficient syn-
thesis of 3-perfluoroalkyl-substituted 7-azaindoles 8a–d
in three steps from 2-halogenopyridines without any chro-
matographic purification. In addition, we disclosed a large
scale preparation to get the valuable building block 12 for
the derivatization in the 4-position with nucleophiles. Its
preparation in four steps contains only a single chromato-
graphic purification, which strongly enhances the value of
our synthesis.
1H NMR (300 MHz, DMSO-d6): d = 7.40–7.44 (m, 1 H), 7.92 (s, 2
H), 8.14–8.20 (m, 1 H), 8.29 (d, J = 4.7 Hz, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 91.2 (dq, JC,F = 32.8 Hz,
3JC,F = 6.2 Hz), 120.3 (d, 2JC,F = 26.0 Hz), 121.6 (d, 3JC,F = 4.5 Hz),
1
4
1H NMR and 13C NMR spectra were recorded in DMSO-d6 at r.t. on
123.0 (q, JC,F = 289 Hz), 141.7 (d, JC,F = 2.8 Hz), 148.6 (d,
3JC,F = 15.1 Hz), 160.1 (d, 1JC,F = 243 Hz).
Bruker Avance spectrometers operating at 300 MHz, 400 MHz and
1
500 MHz for H NMR and 125 MHz for 13C NMR. Flash column
+
HRMS (EI): m/z [M – C2H2F3O2 ] calcd for C7H5F4NO2: 96.0250;
found: 96.0249; m/z [M – CH2F3O+] calcd for C7H5F4NO2:
chromatography was performed on silica gel 60 (0.063–0.200 mm)
purchased from Merck KGaA, Darmstadt, Germany, with the indi-
cated eluent. Solvents for extraction and chromatography were re-
agent grade and used as received. Commercial reagents were used
without purification. Petroleum ether (PE) refers to the fraction
boiling in the range 40–60 °C.
124.0199; found: 124.0198.
2-(2,6-Dichloropyridin-3-yl)-1,1,1-trifluoro-3-nitropropan-2-ol
(6a)
To a solution of freshly prepared LDA (8.56 g, 80 mmol) in THF
(220 mL) at –75 °C, was added a solution of 2,6-dichloropyridine
(10.8 g, 72.7 mmol) in THF (40 mL), and the mixture was stirred
for 2 h at this temperature. To the resulting suspension was added
ethyl trifluoroacetate (15.5 g, 109 mmol) in one portion. The reac-
tion was warmed to r.t. Nitromethane (7.8 mL, 145 mmol) was add-
ed, and the reaction was stirred overnight. The solution was poured
into aq 2 N HCl (1 L), and the mixture was extracted with EtOAc
(2 × 300 mL). The combined organic layers were washed with brine
(300 mL), dried (Na2SO4), and the solvent was evaporated to yield
a brown oil, which was purified by column chromatography on sil-
ica gel (eluent: CH2Cl2) to yield 16.4 g (74%) of the title compound.
2-(2,6-Dichloropyridin-3-yl)-1,1,1-trifluoropropan-2-ol (2)
To a solution of freshly prepared LDA (4.8 g, 44.6 mmol) in THF
(100 mL) at –75 °C, was added a solution of 2,6-dichloropyridine
(6.00 g, 40.5 mmol) in THF (20 mL), and the mixture was stirred
for 2 h at this temperature. Subsequently, trifluoroacetone (6.81 g,
60.8 mmol) was added. The mixture was stirred for 2 h, and then
poured into ice water (300 mL) and extracted with tert-butyl methyl
ether (2 × 100 mL). The combined organic layers were washed with
brine (100 mL), and dried (Na2SO4). The solvent was evaporated
and the crude product obtained was triturated with cyclohexane.
The solid was collected by suction filtration in 57% yield. A second
batch of 1.70 g (16%) was obtained from the mother liquor by crys-
tallization from tert-butyl methyl ether–PE.
1H NMR (300 MHz, DMSO-d6): d = 5.23 (d, J = 14.4 Hz, 1 H),
6.20 (d, J = 14.4 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 8.36 (d,
J = 8.6 Hz, 1 H), 8.46 (s, 1 H).
1H NMR (300 MHz, DMSO-d6): d = 1.95 (s, 3 H), 7.12 (br s, 1 H),
7.66 (d, J = 8.3 Hz, 1 H), 8.32 (d, J = 8.3 Hz, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 74.6 (q, JC,F = 29.7 Hz),
76.2, 123.7 (q, 1JC,F = 289 Hz), 123.9, 129.1, 143.4, 146.6, 149.3.
2
13C NMR (125 MHz, DMSO-d6): d = 21.8, 73.0 (q, JC,F
=
HRMS (EI): m/z [M+] calcd for C8H5Cl2F3N2O3: 303.9629; found:
303.9619.
1
29.6 Hz), 123.4, 125.5 (q, JC,F = 287 Hz), 133.1, 143.1, 147.2,
148.6.
HRMS (EI): m/z [M+] calcd for C8H6Cl2FNO: 258.9779; found:
258.9773.
1,1,1-Trifluoro-2-(2-fluoropyridin-3-yl)-3-nitropropan-2-ol
(6b)
To a solution of freshly prepared LDA (158 g, 1.48 mol) in THF
(3.2 L) at –75 °C was added 2-fluoropyridine (120 g, 1.24 mol), and
the mixture was stirred for 4 h at this temperature. To the resulting
suspension, ethyl trifluoroacetate (246 g, 1.73 mol) was added, dur-
ing which the internal temperature should not rise above –45 °C.
The reaction was warmed to r.t. Nitromethane (134 mL, 2.47 mol)
was added, and the reaction was stirred overnight. The solution was
poured into aq 2 N HCl (17 L), and the mixture was extracted with
EtOAc (2 × 8 L). The combined organic layers were washed with
brine (5 L), dried (Na2SO4), and the solvent was evaporated. The
crystalline residue was triturated with PE, and the product was col-
lected by suction filtration to yield 290 g (92%) of the title com-
pound.
1-(2,6-Dichloropyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol (5a)
To a solution of freshly prepared LDA (517 mg, 4.83 mmol) in THF
(11 mL) at –75 °C, was added 2,6-dichloropyridine (0.65 g,
4.39 mmol), and the mixture was stirred for 1.5 h at this tempera-
ture. Subsequently, ethyl trifluoroacetate (0.75 g, 5.27 mmol) was
added. The reaction was warmed to r.t. and quenched with H2O (30
mL). The mixture was extracted with tert-butyl methyl ether (2 × 30
mL). The combined organic layers were dried (Na2SO4), and the
solvent was evaporated. The crude product was purified by prepar-
ative HPLC to yield 0.27 g (22%) of the title compound.
1H NMR (500 MHz, DMSO-d6): d = 7.45 (d, J = 8.2 Hz, 1 H), 8.10
(s, 2 H), 8.22 (d, J = 8.2 Hz, 1 H).
1H NMR (300 MHz, DMSO-d6): d = 5.10–5.16 (m, 1 H), 5.68 (d,
J = 13.2 Hz, 1 H), 7.25 (ddd, J = 7.7, 4.8, 2.3 Hz, 1 H), 8.27 (ddd,
J = 10.0, 7.7, 1.9 Hz, 1 H), 8.33–8.38 (m, 2 H).
2
13C NMR (125 MHz, DMSO-d6): d = 91.9 (q, JC,F = 32.8 Hz),
123.0, 123.1 (q, 1JC,F = 290 Hz), 131.7, 143.7, 148.3, 149.2.
HRMS (EI): m/z [M – H2O+] calcd for C7H4Cl2F3NO2: 242.9466;
2
13C NMR (125 MHz, DMSO-d6): d = 73.8 (dq, JC,F = 30.0 Hz,
found: 242.9470.
4
2
3JC,F = 6.9 Hz), 77.1 (d, JC,F = 8.3 Hz), 116.7 (d, JC,F = 27.8 Hz),
4
1
122.6 (d, JC,F = 4.2 Hz), 123.8 (q, JC,F = 286 Hz), 141.6 (d,
2,2,2-Trifluoro-1-(2-fluoropyridin-3-yl)ethane-1,1-diol (5b)
To a solution of freshly prepared LDA (2.43 g, 22.7 mmol) in THF
(60 mL) at –75 °C, was added 2-fluoropyridine (2.00 g,
20.6 mmol), and the mixture was stirred for 1.5 h at this tempera-
ture. Ethyl trifluoroacetate (3.51 g, 24.7 mmol) was then added. The
3JC,F = 3.2 Hz), 148.9 (d, 3JC,F = 15.7 Hz), 159.0 (d, 1JC,F = 236 Hz).
HRMS (EI): m/z [M+] calcd for C8H6F4N2O3: 254.0315; found:
254.0321.
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

PAPER
3-Perfluoroalkyl-Substituted 7-Azaindoles
255
3,3,4,4,4-Pentafluoro-2-(2-fluoropyridin-3-yl)-1-nitrobutan-2-
ol (6c)
Analogous to 6b, the title compound was prepared from 2-fluoropy-
ridine (13.0 g, 133 mmol), LDA (160 mmol), methyl pentafluoro-
propionate (33.2 g, 187 mmol) and nitromethane (16.3 g,
267 mmol) in 88% yield as a white solid.
1H NMR (300 MHz, DMSO-d6): d = 5.17 (d, J = 12.8 Hz, 1 H),
5.63 (d, J = 12.8 Hz, 1 H), 7.52 (ddd, J = 7.7, 4.7, 2.3 Hz, 1 H), 8.26
(ddd, J = 10.0, 7.7, 1.7 Hz, 1 H), 8.35 (ddd, J = 4.7, 1.7, 1.1 Hz, 1
H), 8.52 (s, 1 H).
3-(Trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-ol
(7b)
The title compound was synthesized analogously to 7a with Raney-
nickel catalysis from 6b in 81% yield.
Alternative Procedure: Compound 6b (100 g, 393 mmol) was dis-
solved in EtOH (1.5 L) and stirred under H2 (1 atm) with PtO2
(2.23 g, 7.87 mmol) catalyst. After the consumption of the theoret-
ical amount of hydrogen, the solution was filtered, and the filtrate
was refluxed overnight. Subsequently, the solvent was removed un-
der reduced pressure. The residue was dissolved in EtOAc (1 L) and
washed with aq sat. Na2CO3 solution (0.8 L). The aqueous phase
was extracted with EtOAc (0.5 L), and the organic layer was dried
(Na2SO4). The solvent was removed under reduced pressure, and
the oily residue was triturated with CH2Cl2 (0.3 L). The crystalline
product was collected by suction filtration and washed with CH2Cl2
(150 mL) to yield 56.2 g (67%) of the title compound. Additional
4.5 g (6%) was obtained after chromatographic purification (eluent:
CH2Cl2–MeOH, 30:1 to 10:1) of the mother liquor.
2
13C NMR (125 MHz, DMSO-d6): d = 74.2 (dt, JC,F = 23.8 Hz,
1
2
3JC,F = 6.8 Hz), 77.1, 113.4 (tq, JC,F = 267 Hz, JC,F = 34.4 Hz),
116.3 (d, 2JC,F = 28.0 Hz), 118.2 (qt, 1JC,F = 289 Hz,
2JC,F = 35.6 Hz), 122.5 (d, 4JC,F = 4.1 Hz), 141.5 (d, 3JC,F = 2.6 Hz),
149.5 (d, 3JC,F = 15.6 Hz), 159.0 (d, 1JC,F = 236 Hz).
HRMS (EI): m/z [M + CH3CN + H+] calcd for C9H6F6N2O3:
346.0621; found: 346.0633.
1H NMR (400 MHz, DMSO-d6): d = 3.45 (d, J = 11.7 Hz, 1 H),
3,3,4,4,5,5,5-Heptafluoro-2-(2-fluoropyridin-3-yl)-1-nitropen-
tan-2-ol (6d)
Analogous to 6b, the title compound was prepared from 2-fluoro-
pyridine (7.16 g, 73.8 mmol), LDA (88.5 mmol), ethyl heptafluoro-
butyrate (25.0 g, 103 mmol) and nitromethane (9.00 g, 148 mmol)
in 95% yield as a white solid.
3.71 (d, J = 11.7 Hz, 1 H), 6.59 (dd, J = 7.3, 5.1 Hz, 1 H), 6.84 (s, 1
H), 6.97 (s, 1 H), 7.53 (d, J = 7.3 Hz, 1 H), 7.97 (dd, J = 5.1, 1.2 Hz,
1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 52.2, 77.7 (q, JC,F
=
1
29.9 Hz), 112.4, 117.7, 125.3 (q, JC,F = 284 Hz), 132.9, 149.9,
163.4.
1H NMR (300 MHz, DMSO-d6): d = 5.18 (d, J = 12.7 Hz, 1 H),
5.66 (d, J = 12.7 Hz, 1 H), 7.51 (ddd, J = 7.8, 4.7, 2.3 Hz, 1 H), 8.27
(ddd, J = 9.8, 7.9, 1.5 Hz, 1 H), 8.35 (dt, J = 4.7, 1.0 Hz, 1 H), 8.60
(s, 1 H).
HRMS (EI): m/z [M+] calcd for C8H7F3N2O: 204.0510; found:
204.0515.
3-(Pentafluoroethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-
ol (7c)
The title compound was synthesized analogous to 7b in 75% yield.
1H NMR (300 MHz, DMSO-d6): d = 3.45 (d, J = 11.7 Hz, 1 H),
3.76 (d, J = 11.7 Hz, 1 H), 6.60 (dd, J = 7.3, 5.2 Hz, 1 H), 6.87 (s, 1
2
13C NMR (125 MHz, DMSO-d6): d = 75.2 (td, JC,F = 24.3 Hz,
1
2
3JC,F = 6.9 Hz), 77.2, 109.3 (ttq, JC,F = 270 Hz, JC,F = 34.9 Hz,
2JC,F = 34.9 Hz), 114.8 (tt, JC,F = 268 Hz, JC,F = 28.4 Hz), 116.2
1
2
2
1
2
(d, JC,F = 28.3 Hz), 117.1 (qt, JC,F = 288 Hz, JC,F = 34.9 Hz),
122.5 (d, 4JC,F = 4.4 Hz), 141.8, 149.1 (d, 3JC,F = 15.7 Hz), 159.1 (d,
1JC,F = 237 Hz).
H), 7.07 (s, 1 H), 7.58 (d, J = 7.3 Hz, 1 H), 7.98 (dd, J = 5.2, 1.2 Hz,
1 H).
HRMS (EI): m/z [M + CH3CN + H+] calcd for C10H6F8N2O3:
2
396.0589; found: 396.0589.
13C NMR (125 MHz, DMSO-d6): d = 53.6, 78.7 (dd, JC,F
=
=
2
1
2
26.8 Hz, JC,F = 21.7 Hz), 112.6, 114.2 (tq, JC,F = 267 Hz, JC,F
1
2
6-Chloro-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-
b]pyridin-3-ol (7a)
34.7 Hz), 117.7, 119.1 (qt, JC,F = 288 Hz, JC,F = 37.5 Hz), 134.1
(d, 4JC,F = 3.5 Hz), 150.1, 163.3.
Compound 6a (8.03 g, 29.2 mmol) was dissolved in EtOH
(200 mL) and stirred under H2 atmosphere (1 atm) with Raney-
nickel catalysis (1 g). After the consumption of the theoretical
amount of H2, the solution was filtered, and the residue was washed
with EtOH (200 mL). The filtrate was refluxed for 48 h. Et3N
(2.95 g, 29.2 mmol) was added, and heating was continued over-
night. Subsequently, the solvent was removed under reduced pres-
sure. The residue was dissolved in CH2Cl2 (150 mL) and washed
with aq sat. Na2CO3 (100 mL) solution. The aqueous phase was ex-
tracted with CH2Cl2 (2 × 50 mL), and the combined organic layers
were dried (Na2SO4). The solvent was evaporated, and the crude
product was triturated with PE. The crystals were collected by suc-
tion filtration to yield 4.48 g (64%) of the title compound. From the
mother liquor, a second batch of 862 mg (13%) was obtained after
column chromatography on silica gel (eluent: tert-butyl methyl
ether–PE, 1:1).
HRMS (EI): m/z [M+] calcd for C9H7F5N2O: 254.0479; found:
254.0485.
3-(Heptafluoropropyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-
3-ol (7d)
The title compound was synthesized analogous to 7b in 75% yield.
1H NMR (300 MHz, DMSO-d6): d = 3.45–3.52 (m, 1 H), 3.74 (d,
J = 12.3 Hz, 1 H), 6.60 (dd, J = 7.4, 5.2 Hz, 1 H), 6.89 (br s, 1 H),
7.10 (d, J = 1.1 Hz, 1 H), 7.59 (dt, J = 7.4, 1.0 Hz, 1 H), 7.98 (dd,
J = 5.2, 1.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 52.6 (m), 79.7 (dd,
2
2JC,F = 27.8 Hz, JC,F = 22.0 Hz), 109.8 (m), 112.6, 116.0 (tt,
2
1JC,F = 261 Hz, JC,F = 27.8 Hz), 117.6 (qt, 1JC,F = 288 Hz,
2JC,F = 33.8 Hz), 117.8, 134.2 (d, 4JC,F = 3.9 Hz), 150.1, 163.3.
HRMS (EI): m/z [M+] calcd for C10H7F7N2O: 304.0447; found:
304.0448.
1H NMR (500 MHz, DMSO-d6): d = 3.51 (d, J = 11.9 Hz, 1 H),
3.78 (d, J = 11.9 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 7.10 (s, 1 H),
7.37 (s, 1 H), 7.53 (d, J = 7.6 Hz, 1 H).
6-Chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (8a)
Compound 7a (240 mg, 1.01 mmol) was dissolved in CH2Cl2
(8.5 mL) and pyridine (159 mg, 2.02 mmol), and the solution was
cooled to 0 °C. SOCl2 (239 mg, 2.02 mmol) was added, and the
mixture was stirred at r.t. for 2 h, diluted with CH2Cl2 (30 mL) and
poured into ice water (50 mL). The mixture was neutralized (pH 6)
with aq sat. Na2CO3 solution. The aqueous phase was extracted with
2
13C NMR (125 MHz, DMSO-d6): d = 52.61, 77.1 (q, JC,F
=
1
30.2 Hz), 110.9, 116.7, 125.1 (q, JC,F = 284 Hz), 135.5, 150.9,
163.2.
HRMS (EI): m/z [M+] calcd for C8H6ClF3N2O: 238.0121; found:
238.0116.
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

256
H. Schirok et al.
PAPER
1
CH2Cl2 (3 × 30 mL), and the combined organic layers were dried
(Na2SO4). The solvent was removed in vacuo to yield tan crystals
which were triturated with PE and collected by suction filtration to
yield 181 mg (82%) of the title compound 8a.
1H NMR (300 MHz, DMSO-d6): d = 7.32 (d, J = 8.3 Hz, 1 H), 8.10
(d, J = 8.3 Hz, 1 H), 8.20–8.22 (m, 1 H), 12.73 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 105.4 (q, JC,F = 37.4 Hz),
3
1
117.5 118.5, 119.5 (q, JC,F = 2.2 Hz), 123.5 (q, JC,F = 266 Hz),
127.5 (q, 1JC,F = 5.0 Hz), 132.7, 138.5.
HRMS (EI): m/z [M+] calcd for C8H5F3N2O: 202.0354; found:
202.0348.
4-Nitro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine
7-Oxide (10)
2
13C NMR (125 MHz, DMSO-d6): d = 103.5 (q, JC,F = 37.1 Hz),
114.3 (q, 3JC,F = 2.2 Hz), 117.3, 123.9 (q, 1JC,F = 266 Hz), 128.0 (q,
3JC,F = 5.1 Hz), 130.1, 144.8, 146.9.
HRMS (EI): m/z [M+] calcd for C8H4ClF3N2: 220.0015; found:
A solution of 9 (9.00 g, 44.5 mmol) in trifluoroacetic acid (117 mL)
was heated to 70 °C. HNO3 (65%, 6.2 mL, 89 mmol) was added
within 10 min. The reaction was stirred at this temperature for 2 h.
Then it was poured into an ice/water mixture. The precipitate was
collected by suction filtration and washed with H2O. The product
was dried in vacuo to yield 8.32 g (76%) of the title compound.
220.0016.
3-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (8b)
The title compound was synthesized analogous to 8a from 7b
(4.27 g, 20.9 mmol) in CH2Cl2 (200 mL) with pyridine (3.31 g,
41.8 mmol) and SOCl2 (4.97 g, 41.8 mmol) in 83% yield.
1H NMR (500 MHz, DMSO-d6): d = 7.26 (dd, J = 7.9, 4.7 Hz, 1 H),
8.05 (d, J = 7.9 Hz, 1 H), 8.16 (s, 1 H), 8.39 (dd, J = 4.7, 1.3 Hz, 1
H), 12.51 (br s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 8.09 (d, J = 6.9 Hz, 1 H), 8.46
(s, 1 H), 8.49 (d, J = 6.9 Hz, 1H), 14.2 (br s, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 105.5 (q, JC,F = 37.9 Hz),
1
3
110.7, 115.4, 122.6 (q, JC,F = 266 Hz), 132.4, 132.7 (q, JC,F
=
6.5 Hz), 137.0, 141.3.
HRMS (EI): m/z [M+] calcd for C8H4F3N3O3: 247.0205; found:
247.0209.
2
13C NMR (125 MHz, DMSO-d6): d = 102.8 (q, JC,F = 36.8 Hz),
1
3
115.3, 117.2, 124.2 (q, JC,F = 266 Hz), 126.9, 127.2 (q, JC,F
=
5.0 Hz), 144.5, 148.0.
HRMS (EI): m/z [M+] calcd for C8H5F3N2: 186.0405; found:
186.0407.
6-Chloro-4-nitro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyri-
dine (11)
Compound 10 (8.60 g, 34.8 mmol) was dissolved in THF (150 mL).
Hexamethyldisilazane (7.34 mL, 34.8 mmol) was added, and the
mixture was cooled to 0 °C. Trichloroacetyl chloride (15.8 g,
87 mmol) was added dropwise to the mixture, which was subse-
quently warmed to r.t. The mixture was stirred for 2 h, then poured
into H2O (750 mL) and extracted with EtOAc (2 × 300 mL). The
combined organic layers were washed with brine (200 mL) and
dried (Na2SO4). The solvent was evaporated, and the residue was
triturated with PE. The product was collected by suction filtration to
give the desired compound in quantitative yield (9.2 g).
3-(Pentafluoroethyl)-1H-pyrrolo[2,3-b]pyridine (8c)
The title compound was synthesized analogous to 8a in 81% yield.
1H NMR (300 MHz, DMSO-d6): d = 7.26 (dd, J = 7.9, 4.7 Hz, 1 H),
8.00 (d, J = 7.9 Hz, 1 H), 8.12–8.16 (m, 1 H), 8.38 (dd, J = 4.7,
1.5 Hz, 1 H), 12.66 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 100.3 (t, JC,F = 56.8 Hz),
2
113.6 (tq, 1JC,F = 249 Hz, 2JC,F = 39.3 Hz), 116.0 (t, 3JC,F = 3.1 Hz),
1
2
117.4, 119.2 (qt, JC,F = 286 Hz, JC,F = 41.5 Hz), 127.3, 128.4 (t,
1H NMR (500 MHz, DMSO-d6): d = 8.08 (s, 1 H), 8.63 (s, 1 H),
13.62 (s, 1 H).
3JC,F = 7.6 Hz), 144.5, 148.2.
HRMS (EI): m/z [M+] calcd for C9H5F5N2: 236.0373; found:
236.0377.
2
13C NMR (125 MHz, DMSO-d6): d = 102.5 (q, JC,F = 38.2 Hz),
105.2 (q, 3JC,F = 1.8 Hz), 111.6, 129.9 (q, 1JC,F = 266 Hz), 133.6 (q,
3JC,F = 5.7 Hz), 144.3, 148.5, 149.9.
3-(Heptafluoropropyl)-1H-pyrrolo[2,3-b]pyridine (8d)
The title compound was synthesized analogous to 8a in 85% yield.
HRMS (EI): m/z [M+] calcd for C8H3ClF3N3O2: 264.9866; found:
1H NMR (300 MHz, DMSO-d6): d = 7.26 (dd, J = 8.1, 4.7 Hz, 1 H),
7.99 (d, J = 8.1 Hz, 1 H), 8.13–8.16 (m, 1 H), 8.39 (dd, J = 4.7,
1.5 Hz, 1 H), 12.68 (br s, 1 H).
264.9872.
6-Chloro-4-nitro-3-(trifluoromethyl)-1-{[2-(trimethylsi-
lyl)ethoxy]methyl}-1H-pyrrolo[2,3b]pyridine (12)
2
13C NMR (125 MHz, DMSO-d6): d = 100.4 (t, JC,F = 28.7 Hz),
To a solution of 11 (204 g, 634 mmol) and [2-(chloromethoxy)eth-
yl](trimethyl)silane (116 g, 697 mmol) in DMF (2.5 L) was added
NaH (60% suspension in mineral oil, 25.4 g, 634 mmol), and the
mixture was stirred at r.t. for 45 min. The mixture was poured into
brine (12.5 L) and extracted with EtOAc (2 × 4 L). The combined
organic layers were washed with brine (2 L), dried (Na2SO4) and
evaporated. The crude product was purified by column chromatog-
raphy on silica gel (eluent: PE–EtOAc, 95:5) to yield 162 g (65%)
of the title compound.
108.7 (ttq, 1JC,F = 264 Hz, 2JC,F = 36.8 Hz), 115.5 (tt, 1JC,F = 250 Hz,
3
1
2JC,F = 31.7 Hz), 116.2 (t, JC,F = 3.4 Hz), 117.4, 117.8 (qtt, JC,F
=
2
3
288 Hz, JC,F = 21.6 Hz), 127.4, 128.7 (t, JC,F = 8.0 Hz), 144.4,
148.2.
HRMS (EI): m/z [M + H+] calcd for C10H5F7N2: 287.0414; found:
287.0411.
3-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 7-Oxide (9)
A solution of m-chloroperbenzoic acid (335 g, 1.45 mol) in EtOAc
(3 L) was dried (Na2SO4) and cooled to 0 °C. Compound 8b (180 g,
969 mmol) was added in portions. The mixture was stirred for 1 h
during which time white crystals precipitated. They were collected
by suction filtration and washed with EtOAc (600 mL) to yield
155 g (79%) of the desired N-oxide.
1H NMR (400 MHz, DMSO-d6): d = 7.25 (dd, J = 8.0, 6.2 Hz, 1 H),
7.67 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 8.31 (d, J = 6.2 Hz, 1 H),
13.40 (br s, 1 H).
1H NMR (300 MHz, DMSO-d6): d = –0.10 (s, 9H), 0.84 (dd,
J = 8.1, 8.0 Hz, 2 H), 3.58 (dd, J = 8.1, 8.0 Hz, 2 H), 5.70 (s, 2 H),
8.16 (s, 1 H), 8.83 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = –1.51, 17.0, 66.4, 73.9, 102.7
2
3
(q, JC,F = 38.6 Hz), 105.8 (q, JC,F = 1.9 Hz), 112.8, 122.7 (q,
1JC,F = 266 Hz), 136.1 (q, 3JC,F = 6.0 Hz), 145.1, 148.8, 148.9.
HRMS (EI): m/z [M + H+] calcd for C14H17ClF3N3O3Si: 396.0753;
found: 396.0753.
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

PAPER
3-Perfluoroalkyl-Substituted 7-Azaindoles
257
2
3
4-[(6-Chloro-3-(trifluoromethyl)-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1H-pyrrolo[2,3-b]-pyridin-4-yl)oxy]-3,5-difluoro-
aniline (13)
128.6, 129.6 (d, JC,F = 16.4 Hz), 133.0 (d, JC,F = 4.6 Hz), 135.7,
147.6 (d, 3JC,F = 9.1 Hz), 160.0 (d, 1JC,F = 249 Hz), 169.2.
HRMS (EI): m/z [M+] calcd for C15H12FNO4: 289.0750; found:
Compound 12 (71.6 g, 181 mmol) was dissolved in DMSO (0.7 L)
under argon. K2CO3 (75.0 g, 543 mmol) and 4-amino-2,6-difluo-
rophenol (39.4 g, 271 mmol) were added, and the mixture was heat-
ed to 120 °C for 3 h. The mixture was poured into H2O (3.5 L) and
extracted with EtOAc (2 × 1.5 L). The combined organic layers
were washed with brine (1 L), dried (Na2SO4), and the solvent was
evaporated. The crude product was purified by column chromatog-
raphy on silica gel (eluent: PE–EtOAc, 4:1) to yield 69.5 g (78%) of
the desired product.
289.0748.
Benzyl (6-Chloro-3-(trifluoromethyl)-1-{[2-(trimethylsi-
lyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)(2-fluoro-4-
nitrophenyl)acetate (14)
Benzyl (2-fluoro-4-nitrophenyl)acetate (500 mg, 1.73 mmol) was
dissolved in DMF (2.5 mL) and NaH (60% in mineral oil, 69 mg,
1.73 mmol) was added. The mixture was stirred for 30 min at r.t.
Compound 12 (342 mg, 0.86 mmol) was added, and the mixture
was heated to 130 °C for 30 min. The mixture was then poured into
ice water (40 mL) and extracted with EtOAc (4 × 20 mL). The com-
bined organic layers were washed with brine (30 mL) and dried
(Na2SO4). The solvent was evaporated, and the residue was purified
by preparative HPLC to yield 546 mg (99%) of the desired com-
pound as an orange oil.
1H NMR (400 MHz, DMSO-d6): d = –0.11 (s, 9 H), 0.78–0.89 (m,
2 H), 3.58 (t, J = 7.8 Hz, 2 H), 5.24 (d, J = 12.2 Hz, 1 H), 5.30 (d,
J = 12.2 Hz, 1 H), 5.66 (s, 2 H), 5.79 (s, 1 H), 7.00 (s, 1 H), 7.24–
7.28 (m, 2 H), 7.32–7.40 (m, 4 H), 8.05 (dd, J = 8.6, 2.0 Hz, 1 H),
8.23 (dd, J = 9.8, 2.0 Hz, 1 H), 8.58 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = –0.09 (s, 9 H), 0.84 (dd,
J = 8.1, 8.0 Hz, 2 H), 3.58 (dd, J = 8.1, 8.0 Hz, 2 H), 5.62 (s, 2 H),
5.90 (s, 2 H), 6.40 (d, J = 11.0 Hz, 2 H), 6.53 (s, 1 H), 8.39 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = –1.50, 17.0, 66.1, 73.4, 96.9
2
3
2
(dd, JC,F = 23.1 Hz, JC,F = 4.0 Hz), 101.3, 102.9 (q, JC,F
=
38.8 Hz), 104.7 (q, 3JC,F = 1.6 Hz), 117.0 (t, 2JC,F = 16.4 Hz), 123.1
(q, 1JC,F = 266 Hz), 130.2 (q, 3JC,F = 5.6 Hz), 146.7, 148.3, 148.7 (t,
3JC,F = 13.4 Hz), 155.2 (dd, 1JC,F = 244 Hz, 3JC,F = 6.9 Hz), 159.2.
HRMS (EI): m/z [M + H+] calcd for C20H21ClF5N3O2Si: 494.1085;
found: 494.1086.
Benzyl (2-Fluoro-4-nitrophenyl)acetate
13C NMR (125 MHz, DMSO-d6): d = –1.54, 17.0, 46.7, 66.2, 67.7,
2
2
Benzyl tert-butyl malonate (3.00 g, 12.0 mmol) was added drop-
wise to a suspension of NaH (479 mg, 60% in mineral oil,
12.0 mmol) in DMSO (12 mL). The mixture was heated to 100 °C
for 40 min and then cooled to r.t. 3,4-Difluoronitrobenzene
(867 mg, 5.45 mmol) was added. The mixture was stirred at r.t. for
1 h. The solution was poured into a mixture of EtOAc (10 mL), cy-
clohexane (10 mL) and aq sat. NH4Cl solution (50 mL). The aque-
ous phase was extracted with a 1: 1 mixture of EtOAc–cyclohexane
(2 × 100 mL). The combined organic layers were dried (Na2SO4),
and the solvent was evaporated. The remaining residue was purified
by filtration through silica gel (eluent: PE) to yield 1.92 g (89%) of
benzyl tert-butyl (2-fluoro-4-nitrophenyl)malonate as a yellow oil.
73.5, 102.7 (q, JC,F = 37.2 Hz), 111.4 (d, JC,F = 27.2 Hz), 113.7,
4
1
118.1, 120.0 (d, JC,F = 3.2 Hz), 123.5 (q, JC,F = 266 Hz), 128.2,
2
3
128.4, 128.5, 130.7 (d, JC,F = 15.2 Hz), 130.8 (d, JC,F = 3.2 Hz),
3
132.9 (q, JC,F = 5.6 Hz), 135.0, 139.1, 145.7, 147.3, 148.3 (d,
3JC,F = 9.3 Hz), 159.4 (d, 1JC,F = 250 Hz), 168.5.
HRMS (EI): m/z [M + H+] calcd for C29H28ClF4N3O5Si: 638.1496;
found: 638.1509.
3-Fluoro-4-[(3-(trifluoromethyl)-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]aniline (15)
Compound 14 (111 mg, 0.17 mmol) was dissolved in EtOAc
(2.5 mL), and Et3N (35 mg, 0.35 mmol) and 10% Pd/C (40 mg)
were added. The mixture was stirred under a H2 atmosphere for 4 h,
then filtered and the filtrate was washed with aq sat. Na2CO3 solu-
tion (10 mL). The organic layer was dried (Na2SO4), and the solvent
was evaporated to yield 77.7 mg (99%) of the title compound.
1H NMR (400 MHz, DMSO-d6): d = –0.10 (s, 9 H), 0.82 (t,
J = 8.0 Hz, 2 H), 3.57 (t, J = 8.0 Hz, 2 H), 4.12 (s, 2 H), 5.32 (s, 2
H), 5.69 (s, 2 H), 6.34–6.40 (m, 2 H), 6.74 (d, J = 4.9 Hz, 1 H), 6.83
(t, J = 8.7 Hz, 1 H), 8.30 (d, J = 4.9 Hz, 1 H), 8.39 (s, 1 H).
Benzyl tert-Butyl (2-Fluoro-4-nitrophenyl)malonate
1H NMR (400 MHz, DMSO-d6): d = 1.35 (s, 9 H), 5.18–5.26 (m, 2
H), 5.30 (s, 1 H), 7.32–7.41 (m, 5 H), 7.73 (t, J = 8.0 Hz, 1 H), 8.13
(dd, J = 8.6, 2.2 Hz, 1 H), 8.17 (dd, J = 9.8, 2.2 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 27.2, 52.3, 67.1, 82.3, 111.2
2
4
(d, JC,F = 27.5 Hz), 119.5 (d, JC,F = 3.3 Hz), 128.1, 128.2, 128.3
2
3
(d, JC,F = 14.8 Hz), 128.4, 132.1 (d, JC,F = 3.8 Hz), 135.2, 148.1
(d, 3JC,F = 9.2 Hz), 157.7 (d, 1JC,F = 251 Hz), 165.0, 166.2.
13C NMR (125 MHz, DMSO-d6): d = –1.55, 17.0, 30.0, 65.8, 72.8,
+
HRMS (EI): m/z [M – C4H8 ] calcd for C20H20FNO6: 333.0649;
2
2
100.1 (d, JC,F = 24.6 Hz), 102.9 (q, JC,F = 37.1 Hz), 109.9 (d,
found: 333.0659.
4JC,F = 2.1 Hz), 110.4 (d, JC,F = 16.6 Hz), 114.4, 117.6, 124.0 (q,
2
3
Benzyl tert-butyl (2-fluoro-4-nitrophenyl)malonate (698 mg,
1.79 mmol) was dissolved in trifluoroacetic acid (14 mL), and the
mixture was stirred for 30 min at r.t. Volatiles were removed under
reduced pressure to yield benzyl (2-fluoro-4-nitrophenyl)acetate as
a slightly tan solid in quantitative yield.
1JC,F = 266 Hz), 130.8 (q, 3JC,F = 6.2 Hz), 131.5 (d, JC,F = 6.5 Hz),
3
142.5, 144.8, 147.7, 149.7 (d, JC,F = 11.4 Hz), 161.2 (d,
1JC,F = 241 Hz).
HRMS (EI): m/z [M+] calcd for C21H25F4N3OSi: 439.1703; found:
439.1701.
Benzyl (2-Fluoro-4-nitrophenyl)acetate
1H NMR (300 MHz, DMSO-d6): d = 4.00 (s, 2 H), 5.16 (s, 2 H),
7.30–7.40 (m, 5 H), 7.71 (t, J = 7.8 Hz, 1 H), 8.09 (d, J = 9.9 Hz, 1
H), 8.17 (d, J = 8.5 Hz, 1 H).
Acknowledgment
We are grateful to Dr. P. Schmitt, C. Streich and D. Bauer for recor-
ding NMR spectra. In addition, we thank H. Musche, S. Brauner, M.
Stoltefuß and G. Wiefel-Hübschmann for HRMS measurements,
and acknowledge the DTA determinations by Dr. D. Heitkamp.
13C NMR (125 MHz, DMSO-d6): d = 33.9, 66.2, 110.8 (d,
4
2JC,F = 27.2 Hz), 119.4 (d, JC,F = 3.4 Hz), 127.8, 128.0, 128.4,
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York

258
H. Schirok et al.
PAPER
(11) Sauter, F.; Stanetty, P.; Ramer, W.; Sittenthaler, W.
References
Monatsh. Chem. 1991, 122, 879.
(1) Current address: Sigma-Aldrich Production GmbH,
Industriestraße 25, 9471 Buchs, Switzerland.
(12) (a) Cook, D. J.; Pierce, O. R.; McBee, E. T. J. Am. Chem.
Soc. 1954, 76, 83. (b) Imperiali, B.; Abeles, R. H.
Tetrahedron Lett. 1986, 27, 135. (c) Solladie-Cavallo, A.;
Khiar, N. Tetrahedron Lett. 1988, 29, 2189. (d) Blades, K.;
Butt, A. H.; Cockerill, G. S.; Easterfield, H. J.; Lequeux, T.
P.; Percy, J. M. J. Chem. Soc., Perkin Trans. 1 1999, 3609.
(13) Colin, T.; El Kaïm, L.; Gaultier, L.; Grimaud, L.; Gatay, L.;
Michaut, V. Tetrahedron Lett. 2004, 45, 5611.
(2) Reviews: (a) Park, B. K.; Kitteringham, N. R.; O’Neill, P.
M. Ann. Rev. Pharmacol. Toxicol 2001, 41, 443. (b) Ismail,
F. M. D. J. Fluorine Chem. 2002, 118, 27. (c) Kirsch, P.
Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim,
2004, 237–271. (d) Böhm, H.-J.; Banner, D.; Bendels, S.;
Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637. (e) Dolensky, B.; Nam, G.;
Deng, W.-P.; Narayanan, J.; Fan, J.; Kirk, K. L. J. Fluorine
Chem. 2004, 125, 501. (f) Shimizu, M.; Hiyama, T. Angew.
Chem. Int. Ed. 2005, 44, 214; Angew. Chem. 2005, 117,
218. (g) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006,
127, 303.
(14) The product 3a itself melted above 80 °C and decomposed
starting at 135 °C (2150 kJ/kg).
(15) Wu, G.; Huang, M.; Richards, M.; Poirier, M.; Wen, X.;
Draper, R. W. Synthesis 2003, 1657.
(16) Sutter, P.; Weis, C. D. J. Heterocycl. Chem. 1987, 24, 1093.
(17) (a) Hojo, M.; Masuda, R.; Okada, E.; Miya, H. Synthesis
1989, 550. (b) Hojo, M.; Masuda, R.; Okada, E.; Tomifuji,
T.; Imazaki, N. Synthesis 1990, 1135. (c) Okada, E.;
Masuda, R.; Hojo, M.; Imazaki, N.; Miya, H. Heterocycles
1992, 34, 103.
(18) (a) Okada, E.; Tsukushi, N.; Shimonura, N. Synthesis 2000,
237. (b) Rodrigues, I.; Bonnet-Delpon, D.; Béqué, J.-P.
J. Org. Chem. 2001, 66, 2098.
(19) Figueroa-Pérez, S.; Bennabi, S.; Schirok, H.; Thutewohl, M.
Tetrahedron Lett. 2006, 47, 2069.
(20) Schneller, S. W.; Lua, J.-K. J. Org. Chem. 1980, 45, 4045.
(21) (a) Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.;
Grifantini, M.; Martelli, S. J. Med. Chem. 1982, 25, 1258.
(b) Meade, E. A.; Beauchamp, L. M. J. Heterocycl. Chem.
1996, 33, 303.
(3) Jeschke, P. ChemBioChem 2004, 5, 570.
(4) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432; Angew.
Chem. 2006, 118, 5558.
(5) Recently, we described an alternate access to 4-chloro-3-
trifluoromethyl-7-azaindole: Ebenbeck, W.; Figueroa-
Pérez, S.; Schirok, H. US Patent application 2006/0128661,
2006; Chem. Abstr. 2006, 145, 62868.
(6) (a) Schirok, H. Synlett 2005, 1255. (b) Schirok, H. J. Org.
Chem. 2006, 71, 5538.
(7) (a) Güngör, T.; Marsais, F.; Quéguiner, G. J. Organomet.
Chem. 1981, 215, 139. (b) For a review, see: Mongin, F.;
Quéguiner, G. Tetrahedron 2001, 57, 4059.
(8) Bobbio, C.; Schlosser, M. J. Org. Chem. 2005, 70, 3039; and
references cited therein.
(9) (a) Tarrant, P.; Taylor, R. E. J. Org. Chem. 1959, 24, 238.
(b) Jiang, B.; Xu, Y. J. Org. Chem. 1991, 56, 7336.
(c) Nader, B. S.; Cordova, J. A.; Reese, K. E.; Powell, C. L.
J. Org. Chem. 1994, 59, 2898. (d) Pan, R.-Q.; Liu, X.-X.;
Deng, M.-Z. J. Fluorine Chem. 1999, 95, 167. (e) Jiang, B.;
Wang, Q.-F.; Yang, C.-G.; Xu, M. Tetrahedron Lett. 2001,
42, 4083. (f) Lebel, H.; Paquet, V. Org. Lett. 2002, 4, 1671.
(10) Salvador, R. L.; Saucier, M.; Simon, D.; Goyer, R. J. Med.
Chem. 1972, 15, 646.
(22) For a systematic survey of chlorination agents on 7-aza-
indole N-oxide, see: Benoit, S.; Gingras, S.; Soundararajan,
N. Patent application WO 03/082289, 2003; Chem. Abstr.
2003, 139, 307795.
(23) Kobayashi, Y.; Kumadaki, I.; Hirose, Y.; Hanzawa, Y.
J. Org. Chem. 1974, 39, 1836.
(24) Qiu, J.; Stevenson, S. H.; O’Beirne, M. J.; Silverman, R. B.
J. Med. Chem. 1999, 42, 329.
Synthesis 2007, No. 2, 251–258 © Thieme Stuttgart · New York