Fluoroazaindolines by an uncommon radical ipso-substitution of a C-F bond

Article abstract of DOI:10.1071/CH10422

Trifluoroazaindoline derivatives are prepared using the first synthetically useful radical ipso-substitution of a fluorine atom. The initial procedure has been improved to allow the gram scale synthesis of these building blocks, which can be regioselectiv

Full text of DOI:10.1071/CH10422

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 416–425
www.publish.csiro.au/journals/ajc
Fluoroazaindolines by an Uncommon Radical
ipso-Substitution of a C-F Bond
A
A
A
A B
,
Yann Laot, Laurent Petit, Ngoc Diem My Tran, and Samir Z. Zard
A
Laboratoire de Synthe`se Organique, UMR 7652 CNRS/Ecole Polytechnique,
91128 Palaiseau, France.
B
Corresponding author. Email: zard@poly.polytechnique.fr
Trifluoroazaindoline derivatives are prepared using the first synthetically useful radical ipso-substitution of a fluorine
atom. The initial procedure has been improved to allow the gram scale synthesis of these building blocks, which can be
regioselectively substituted by nucleophiles under mild conditions to rapidly access a library of new molecules. Oxidation
to the corresponding fluoroazaindole core has also been accomplished.
Manuscript received: 22 November 2010.
Manuscript accepted: 27 January 2011.
Introduction
presence of a fluorine atom would block cyclizations on the
carbon and force the radical to attack on the pyridine nitrogen,
independently of the nature of the substituent on the extra-
nuclear nitrogen atom.[5]
The reversible radical addition-fragmentation of xanthates
and related thiocarbonylthio derivatives has proven to be a
uniquely powerful synthetic tool.[1] Many reputedly difficult
radical-based transformations including intermolecular addi-
tions to unactivated olefins and ring-closures onto aromatic
and heteroaromatic systems can now be readily accomplished.
It is thus possible to construct 5, 6 and 7-membered rings by a
direct radical closure onto a pyridine nucleus.[2] In the course
of this work, we found that whereas N-acetyl protected xan-
thate 1a underwent the expected cyclization into azaindoline
2a in good yield, the corresponding N-Boc derivative 1b
furnished only a small yield of the corresponding azaindoline
2b. The main product turned out to be pyridinone 3 arising by a
hitherto undocumented radical attack on the pyridine nitrogen
(Scheme 1). Further work revealed that the Boc group may be
replaced by a smaller carbamate fragment and the chlorine
in the pyridine ring may be exchanged for a fluorine, but no
completely satisfactory rationale for this unexpected behav-
iour has emerged so far.[3,4] A similar difference in reactivity
was recently observed in the pyrimidine series.[3b] In an
attempt to expand the scope of the process and gain a better
understanding of the underlying factors, we examined the case
of fluorinated derivative 6 (Scheme 2). We hoped that the
Results and Discussion
Compound 6 was readily prepared by radical addition of
xanthate 5a to protected N-allylaminopyridine 4, itself obtained
from the commercially available pentafluoropyridine by
substitution, first with dimethylamine then with allylamine
followed by reaction with Boc anhydride.[6]
Exposure of xanthate 6 to the action of lauroyl peroxide
(DLP) did not yield any of the expected pyridone 7. Instead, a
modest yield of azaindoline 8 was observed. Clearly, cyclization
occurred at carbon with loss of a fluorine atom and, surprisingly,
a methyl group was somehow concomitantly cleaved from the
dimethylamino substituent on C-4.
A plausible mechanistic rationale for this unusual transfor-
mation is presented in Scheme 3. Cleavage of the xanthate
group produces radical 9, which undergoes cyclization on C-5 to
give intermediate 10. This is then oxidized into the correspond-
ing allylic cation 11 by electron transfer to the peroxide.
This species is, on one hand, destabilized by the adjacent
S
EtO
R
Lauroyl
peroxide
Lauroyl
peroxide
S
N
R
O
N
O
N
X
N
X
N
N
Rꢁ ꢂ ORꢀ
ORꢀ
O
Rꢁ
Rꢁ
O
R
1a Rꢁ ꢂ Me
1b Rꢁ ꢂ ORꢀ
2a Rꢁ ꢂ Me
2b Rꢁ ꢂ ORꢀ
3
X ꢂ Cl, F
Scheme 1. Divergent radical cyclization on a pyridine ring.
Ó CSIRO 2011
10.1071/CH10422
0004-9425/11/040416

RESEARCH FRONT
Fluoroazaindolines
417
electron-withdrawing fluorine atoms but, on the other, it is
stabilized by interaction with the electron lone pairs on the
two exocyclic nitrogen substituents. Elimination of hydrogen
fluoride then leads to the iminium derivative 12, which is readily
hydrolyzed upon work-up into novel difluoroazaindoline 8.
The radical closure on a carbon bearing a fluorine atom on
the pyridine ring raised the question of the evolution of the
cyclized radical in the absence of a second nitrogen substituent
to stabilize the corresponding cation. To address this question,
xanthate 14 derived from N-Boc-N-allyl-4-aminotetrafluoro-
pyridine 13 was treated with stoichiometric amounts of DLP
in refluxing ethyl acetate. The reaction was not very clean but
trifluoroazaindoline 17 could be isolated in a somewhat
impure state in ,40% yield (by NMR; Scheme 4).
The formation of this new azaindoline apparently implies the
homolytic rupture of a very strong C-F bond in intermediate 16.
Fragmentation of a C-F bond under such mild conditions is
exceedingly rare,[7] in contrast to the b-scission of chlorides,
bromides and iodides, which is well documented.[8] The decom-
position of peroxides in perfluorinated aromatic solvents has
been reported to give products that could arise by a homolytic
ipso-substitution of a carbon-fluorine bond.[7] The yields were
generally low and considerable amounts of dimers of the
intermediate perfluorocyclohexadienyl radicals were observed.
Interestingly, the various mechanistic rationales put forward
in these early studies do not explicitly invoke homolysis with
elimination of a fluorine atom, as this must have been deemed
too unlikely in view of the strength of the C-F bond. A
favourable entropic term and the re-aromatization of the pyri-
dine ring may nevertheless constitute a sufficient driving force
to break the strong C-F bond and to expel a fluorine atom as
outlined in Scheme 4. The nucleophilic character of adduct
radical 15 and the electrophilic character of the pyridine ring are
complementary, which should increase the rate of the cycliza-
tion and the overall efficiency. Previous studies, especially by
Walton and Studer, have demonstrated the possibility of break-
ing strong C-C and C-O bonds in similar structures.[9] Cleavage
of the stronger C-F bond in the same manner, while obviously
more difficult, is therefore not unrealistic.
S
Me
Me
Me
Me
N
N
N
N
EtO
S
CN
F
F
F
F
NC
S
5a
F
N
F
N
Lauroyl peroxide
AcOEt, reflux
OEt
O-tBu
tBuO
78%
O
4
O
S
6
(1) Me2NH
(2) H2N
(3) Boc2O
Lauroyl
peroxide
Me
Me
N
N
F
F
F
O
CN
F
F
F
F
Me
O
N
NH
N
O-tBu
F
An alternative route can be considered involving first a
solvolysis to give radical-cation 18-189 and a fluoride anion,
followed by quenching with a nucleophile in the medium such
as water or lauric acid (R0OH) leading to radical 19.[10] This is
then followed by homolytic b-scission to give the observed
azaindoline 17. Even if this variant cannot yet be discounted, it
seems nevertheless highly unlikely, owing to the poor leaving
N
7
N
F
NC
O-tBu
O
8
40%
Scheme 2. Unexpected radical ipso-cyclization-demethylation.
Me
Me
Me
Me
N
N
4
3
DLP (stoich.)
AcOEt reflux
F
F
NC
S
F
F
NC
5
2
6
F
N
N
F
N
N
•
OEt
Me
tBuO
O
O
O-tBu
S
9
6
H
F
CN
CN
Me
CN
Me
Me
Me
F
N
N
N
•
F
F
DLP
F
F
•ꢃ
N
N
N
F
N
F
N
F
N
[DLP]
O-tBu
CN
O-tBu
O-tBu
CN
11
10
O
O
O
HF
OH
CN
Me
Me
Me
NH
N
N
F
F
F
F
H2O
O-tBu
N
N
N
N
F
F
N
N
O-tBu
HCHO
O-tBu
8
12
12
O
O
O
Scheme 3. Plausible mechanism for the radical cyclization-demethylation.

RESEARCH FRONT
418
Y. Laot et al.
group ability of the fluoride anion and the low dielectric
constant of the solvent, which should disfavour such a hetero-
lytic pathway (a naked fluoride anion is a strong base and
therefore a recalcitrant nucleofuge). Interestingly, Shoute
and Mittal generated a radical-anion from hexafluorobenzene
through radiolysis and noted the relative difficulty of elimi-
nating fluoride anion.[11] Eliminating fluoride from a simple
free radical (in contrast to the radical anion in Shoute and
Mittal’s work) should therefore be even more difficult. These
authors further remarked on the ‘considerable resistance’ of
hexafluorobenzene to radical addition. Both of these observa-
tions make the present cyclization and extrusion of a fluorine
atom all the more unique.
Yet another mechanistic route hinges on a possible abstrac-
tion by intermediate radical 16 of a hydrogen atom from the
solvent to give derivative 20. This can then ionically lose
hydrogen fluoride to furnish the observed product 17. However,
radical 16 is highly stabilized: it is both tertiary and allylic, and
further stabilized by the lone pair of the nitrogen. Its reaction
with the solvent would be expected to be very endothermic and
in fact quite unlikely. The possibility of a prior ionic elimination
of HF from 16 followed by hydrogen abstraction from the
solvent is even less likely. Ionic elimination of HF from 16
in the absence of a base in a non-polar solvent is too slow in
comparison with the lifetime of the radical. In addition, the
resulting radical species would still be too stabilized and
incapable of hydrogen abstraction from the solvent.
From a synthetic perspective, we found this reaction capri-
cious, giving variable and often low yields. The observation by
NMR of unidentified side products where the Boc group had
apparently been lost indicated a likely deleterious effect of the
hydrogen fluoride produced through any of the mechanistic
pathways discussed above. The Boc group in 14 was therefore
replaced with the more robust acetyl group, which allowed
us to operate at the much higher temperature of refluxing
o-dichlorobenzene (1758C).
The higher temperature improves the chances of an intrinsi-
cally difficult cyclization and favours the fragmentation step,
which has a large entropic term.[12] At this temperature, lauroyl
peroxide must be replaced with di-tert-butyl peroxide. Under
these conditions, the reaction was more reproducible and clean-
er, furnishing the desired trifluoroazaindoline 23a in 50% yield
along with 25% of prematurely reduced material (24, R ¼ Me).
Unfortunately, the formation of this side product could not be
avoided. It should be noted that as the intermolecular radical
addition usually necessitates the use of an excess of xanthate, it
is better to purify the xanthate adduct to avoid side reactions
during the radical cyclization.
S
OEt
S
N
O
CN
O
O
CN
R
F
R
F
N
N
R
F
N
N
NC
S
OEt
F
F
F
F
F
S
DLP
5a
DLP, AcOEt
F
N
F
F
F
15
13–R ꢂ OtBu
21–R ꢂ Me
14–R ꢂ OtBu
22a–R ꢂ Me
CN
N
(1) H2N
(2) Boc2O or Ac2O
O
O
NC
N
R
F
R
F
F
F
F
F
F
F
F
F
N
F
N
F
F
N
O
16
24
R
F
N
O
ꢃF
ꢃF
O
NC
R
N
NC
CN
R
N
F
F
N
F
H
ꢃHF
F
F
18
F
F
F
N
F
O
N
17–R ꢂ OtBu 39%
23a–R ꢂ Me 50%
NC
R
20
RꢁOH
N
O
F
F
ꢃRꢁO
ꢃH
CN
R
N
N
F
F
18؅
ORꢁ
F
N
F
19
Scheme 4. Azafluoroindoline by a radical ipso-cyclization and fluorine atom elimination.

RESEARCH FRONT
Fluoroazaindolines
419
EtO
S
S
N
O
O
R
O
N
N
N
S
OEt
R
R
F
F
F
F
F
F
F
F
F
S
tBuO-OtBu
F
N
O
F
N
DLP, AcOEt
Reflux
C6H4Cl2
Reflux
O
O
O
N
MeO
N
N
N
PhthN
O
O
F
F
F
F
F
F
O
F
N
F
N
F
N
23d (95; 40)
23b (80; 45)
23c (78; 45)
O
N
O
O
N
Bn
N
N
PhO
Cl
N
N
F
F
F
F
N
O
O
F
N
F
N
F
F
N
F
23e (60; 27)
23f (60; 43)
23g (80; 50)
O
N
O
O
OMe
N
Me
CO2Et
CF3
Me
N
N
EtO2C
AcHN
F
F
F
F
O
F
N
F
F
N
F
N
F
23h (62; 32)
23i (74; 41)
23j (74; 51)
Scheme 5. Preparation of trifluoroazaindolines.
Various trifluoroazaindolines were prepared in the same
manner as shown by the results collected in Scheme 5 (the
yields in brackets refer to the intermolecular addition and to the
subsequent cyclization). Xanthates bearing various functional
groups added readily to the terminal alkene in 21 ultimately
allowing access to a broad assortment of novel trifluoroazain-
dolines. Even if the yields of the cyclization step are generally
modest, the approach described herein is concise and conver-
gent, and provides access to a family of hitherto unknown
fluoroazaindolines which would be difficult to obtain otherwise.
It is one of the distinguishing features of the xanthate-based
technology that the intermediate radicals have enough lifetime
to partake in relatively slow processes such as the present ipso-
closure on a fluorine substituted pyridine ring.
point of amyl acetate (1508C), the peroxide can be added all at
once at the beginning and the mixture simply heated to reflux
until complete consumption of the starting material. The
solvent is then evaporated and the residue purified by flash
chromatography. Several grams of azaindoline 23a were
prepared using this simplified procedure, allowing us to
explore some of its chemistry. The fluorine atom at position
2 could be easily and regioselectively substituted by various
nucleophiles. The fluorines at positions 3 and 6 were not
affected under the reaction conditions. Both of these positions
are hindered by the fused dihydropyrrole ring, and the
3-fluorine is in a position that is not activated by the nitrogen
of the pyridine nucleus.[13] Various amines reacted readily as
shown by the examples in Table 1.
The reaction conditions used to prepare the indolines
displayed in Scheme 5 did not prove very convenient for
multigram scale synthesis. The medium at the end of the
heating period was dark and purification was somewhat
laborious. After some experimentation in the case of 23a,
we found that replacing o-dichlorobenzene with n-amyl ace-
tate gave a much improved reaction medium (clear yellow
instead of almost black) even if the yield was the same as in
o-dichlorobenzene. Furthermore, because of the lower boiling
Primary amines gave a moderate yield (entries 1, 2), presum-
ably because of competing side reactions involving the nitrile
and acetyl groups. In contrast, secondary amines furnished the
substitution products in high yield (entries 3–6).
Using NaH as base and DMF as solvent, imidazole reacted
relatively cleanly (entry 7) as did phenol and thiophenol (entries
8, 9). Under those basic conditions, the N-acetyl group was
cleaved when imidazole and phenol were used as nucleophiles
(entries 7, 8). Interestingly, methanol reacted in the presence of

RESEARCH FRONT
420
Y. Laot et al.
CN
CN
Table 1. Method A: 2.2 equiv. nucleophile, DMF, 508C; Method B:
3.0 equiv. nucleophile, DMF, r.t.; Method C: 3.0 equiv. nucleophile,
NaH, DMF, r.t.; Method D: MeOH, K2CO3, r.t.
NH
F
NH
F
F
IBX (5 equiv.),
DMSO, 50ꢄC, 24h
F
N
F
F
N
25j
50%
Entry Nucleophile (method)
Product (25a–j)
Yield
26
O
N
O
CN
NH
N
OH
NC
NC
H2N
F
F
F
F
1
25a 28
(1) Morpholine, DMF, r.t.
(B)
OH
F
N
N
F
N
F
N
N
(2) K2CO3, MeOH, r.t.
69%
H
O
23a
27
O
IBX (2 equiv.),
DMSO, r.t., 2h
31%
N
NC
CN
NH
F
H2N
2
25b 43
(A)
F
F
N
N
H
F
N
N
O
28
O
N
HN
NC
NC
NC
F
Scheme 6. IBX mediated oxidation to fluoroazaindoles.
3
25c 81
(B)
F
N
N
potassium carbonate resulting in almost quantitative cleavage of
the acetyl side chain without substitution of any of the fluorine
atoms (entry 10).
O
Azaindolines and related derivatives are emerging as impor-
tant pharmacophores in medicinal chemistry, especially as
kinase inhibitors for the treatment of cancer.[14] The present
short route to substituted fluoroazaindolines is convergent and
easily amenable to the synthesis of libraries of very diverse
structures. Furthermore, the selective cleavage of the acetyl
group in 23a with methanol/K2CO3 raised the possibility of
oxidation of the azaindoline core into an azaindole. Azaindoles
are also of great importance in medicinal chemistry as demon-
strated by the large number of publications dealing with their
synthesis.[15]
Disappointingly, our initial attempts at completely aromatiz-
ing the azaindoline ring were met with failure. Standard
oxidizing agents, such as MnO2, DDQ, cobalt-salen complex,
Pd/C-air, cerium ammonium nitrate or trichloroisocyanuric
acid,[16] which are effective with ordinary indolines and azain-
dolines, left compound 25j unscathed. Clearly, the presence of
the three electronegative fluorine atoms strongly deactivates the
dihydropyrrole fragment with respect to oxidation. Ultimately,
we found that an excess of o-iodoxybenzoic acid (IBX) in
DMSO at 508C, as described by Nicolaou et al.[17] accomplished
the desired oxidation and furnished azaindole 26 in a reproduc-
ible 50% yield. Using the same conditions, we could also
aromatize morpholine-substituted azaindoline 27. Owing to
the presence of the electron donating morpholine substituent,
the oxidation process was faster, but the yield of azaindole 28
was only a modest 31% (Scheme 6). It is noteworthy that
manganese dioxide failed to accomplish the oxidation even in
this more favourable case.
N
HN
F
O
4
25d 81
25e 94
25f 84
(B)
F
N
N
O
O
N
HN
F
5
(B)
F
N
N
O
N
Me
HN
NC
NC
F
Me
6
Me
(B)
F
F
N
N
Me
NH
N
H
N
F
7
8
25g 58
N
N
(C)
N
NH
N
NC
NC
HO
F
25h 60
F
OPh
(C)
(C)
O
N
HS
As a further extension of this approach, we examined the
possibility of preparing fluoroazaoxindole derivatives by cycli-
zation of xanthates such as 29, which are very easily available
from pentafluoropyridine as shown in Scheme 7. In the event,
treatment of xanthate 29 with di-tert-butylperoxide under the
same conditions did not afford the expected azaoxindole;
instead, the reduced amide 32 was produced. Performing the
reaction in refluxing o-dichlorobenzene gave the azaoxindole 33
in very low yield (o15%) along with the reduced amide.
F
9
25i 61
F
N
SPh
NH
NC
F
F
MeOH
(D)
10
25j 97
F
N

RESEARCH FRONT
Fluoroazaindolines
421
O
N
O
Me
S
OEt
F
F
F
N
N
(1) MeNH2
(2) BrC(O)CH2Br
(3) KSC(S)OEt
NC
S
OEt
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
S
S
29
N
F
DLP, AcOEt
79%
83% (3 steps)
F
34
S
OEt
Di-tert-butylperoxide
o-Dichlorobenzene, reflux
NC
S
O
N
O
N
O
O
NC
Di-tert-butylperoxide
F
F
F
F
F
Me
Me
N
N
Me
Amyl acetate
23%
N
N
Reduction
F
F
F
F
F
F
F
F
F
F
F
36
35
30
32
33
F
Scheme 8. Inefficiency of the radical cyclization onto a perfluorobenzene
ring.
O
N
O
Me
Me
N
F
F
F
F
boiling between 40–608C. Flash chromatography was per-
formed on silica gel as the stationary phase. Thin-layer chro-
matography (TLC) was performed on alumina plates pre-coated
with silica gel, which were visualized by the quenching of UV
fluorescence (lmax ¼ 254 and/or 366 nm) and/or by staining
with vanillin in acidic ethanol followed by heating. Infrared
spectra were recorded as solutions in CCl4 using CaF2 cells.
F
N
F
N
F
ꢃF
31
ꢅ15% yield
Scheme 7. Attempted preparation of a trifluoroazaoxindole core.
In an earlier work,[2] we found that in the absence of the
Absorption maxima (nmax) are reported in wavenumbers [cmꢀ1
]
adjacent fluorine atoms, the cyclization proceeds smoothly. In
the present case, and because of the greater stability of interme-
diate radical 30 in comparison to radical 15, the equilibrium
between the opened and closed radicals 30 and 31 favours
the former. Ultimately, hydrogen abstraction from the medium
gives predominantly acetamide 32 as observed.
Finally, we confirmed that the radical ipso-substitution of a
fluorine atom is indeed a far from trivial transformation by
studying the corresponding fluorobenzene analogue 35. As
depicted in Scheme 8, this compound was prepared from
hexafluorobenzene by adapting a literature procedure (30%
over two steps, non-optimized)[18] to obtain N-allyl acetamide
34 followed by the usual radical addition to the terminal alkene
(79% yield). Treatment of the resulting xanthate 35 with the
peroxide in refluxing n-amyl acetate furnished the expected
indoline 36 but in a somewhat impure state and in a low 23%
yield (by NMR).
and only selected peaks are reported. Proton magnetic resonance
spectra (1H NMR) were recorded at 400 MHz and coupling
constants (J) are reported to ꢁ0.5 Hz. The following abbrevia-
tions were used to describe peak patterns when appropriate:
br ¼ broad; s ¼ singlet; d ¼ doublet; t ¼ triplet; q ¼ quartet; and
m ¼ multiplet. Carbon magnetic resonance spectra (13C NMR)
were recorded at 100.6 MHz. The signals related to the O-ethyl
xanthate group are described as: CH2-Xa and CH3-Xa. Chemi-
cal shifts (dH, dC) are quoted in parts per million [ppm] and are
referenced to the residual solvent peak (CDCl3: dH ¼ 7.26 and
dC ¼ 77.0 ppm). Low-resolution mass spectra (m/z) were
recorded by chemical ionization (CI/NH3) and only report mo-
lecular species ([MþH]þ, [MþNH4]þ) and other major frag-
ments. High-resolution mass spectra were recorded by positive
electron impact ionization (EIþ) at 70 eV. The quoted masses
are accurate to ꢁ5 ppm.
General procedure for the intermolecular addition of
xanthate: A solution of olefin (n mmol) and xanthate
(2 n mmol) in ethyl acetate (0.5–1.0 n mL) was refluxed for
10 min under a nitrogen atmosphere and 10 mol% of DLP was
added. After 90 min, an additional 5 mol% portion was added,
then every 90 min until complete consumption of the olefin.
The mixture was then cooled to room temperature and the
solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography on silica gel to yield
the corresponding xanthate.
General procedure for the radical cyclization: A solution
of xanthate (n mmol) in n-amyl acetate (15 n mL) was refluxed
for 10 min under a nitrogen atmosphere. Di-tert-butylperoxide
(2–5 n mmol) was then added at once. The solution was stirred at
reflux until complete consumption of the starting xanthate. The
mixture was allowed to cool to room temperature and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel to yield the desired
compounds.
It is likely that, in this case, it is the cyclization step that is
rather inefficient, since the elimination of the fluorine atom
should be at least as rapid as in the pyridine series.
Conclusion
In summary, we have described an easy entry into an uncommon
class of fluorinated heterocyclic derivatives that could be
of interest to the pharmaceutical and agrochemical indus-
tries.[19] Some unusual reactivities were uncovered, such as the
demethylation reaction observed in the synthesis of compound 8
and, more importantly, the homolytic rupture of a very strong
C-F bond. A better understanding of the factors that govern these
processes should allow us to improve the yields and perhaps
expand the scope.
Experimental
The solvents were used as supplied by commercial sources.
Petroleum ether refers to the fraction of light petroleum ether,

RESEARCH FRONT
422
Y. Laot et al.
General Procedures for the Aromatic Nucleophilic
Substitution Reactions
ethyl acetate 7:3 to 3:7) gave compound 25b (26.5 mg, 43%).
max (CCl4)/cmꢀ1 2928, 1686, 1650, 1558, 1542. dH (400 MHz,
n
CDCl3) 5.05 (s, 1H), 4.20 (dd, J 11.3, 8.6, 1H), 3.97 (dd, J 11.4,
3.8, 1H), 3.40 (br s, 1H), 2.76 (m, 1H), 2. 42 (m, 2H), 2.29 (2s,
3H), 2.09 (m, 1H), 1.92 (m, 1H), 0.84 (d, J 5, 2H), 0.55 (m, 2H).
dC (100.6 MHz, CDCl3) 168.9 (CO), 118.7 (CN), 56.3 (CH2),
35.8 (CH), 29.2 (CH2), 24.0 (CH), 23.4 (CH3), 14.8 (CH2), 7.3
(2CH2). m/z (HR-EIþ) calc. for C15H16F2N4O 306.1292, found
306.1299.
Methods A, B and C: To a solution of trifluoroazaindoline 23a
(n mmol) in DMF (2–5 n mL) was added the appropriate
nucleophile (2–5 n mmol) (for method C: 3–6 n mmol of NaH
was then added at room temperature). The mixture was stirred at
508C (method A) or at room temperature (method B) until
complete consumption of the trifluoroazaindoline. Water and
ethyl acetate were then added and the aqueous layer was
extracted twice. The organic layer was washed with brine, dried
(MgSO4), filtered and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography on
silica gel to yield the desired difluoroazaindolines.
Method D: The fluoroazaindoline (n mmol) was dissolved
in MeOH (n mL) and K2CO3 (4–5 n mmol) was added at room
temperature. The mixture was then stirred until consumption of
the starting material. Water and ethyl acetate were added and
the aqueous layer was extracted twice. The organic layer was
dried (MgSO4), filtered, and the solvent was removed under
reduced pressure. The residue was purified by flash chromato-
graphy on silica gel to yield the corresponding unprotected
fluoroazaindoline.
3-(1-Acetyl-4,7-difluoro-6-(piperidin-1-yl)-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25c)
Following method B, the reaction was carried out using
trifluoroazaindoline 23a (30 mg, 0.11 mmol, 1.0 equiv.) and
piperidine (32 mL, 0.33 mmol, 3.0 equiv.) in DMF (0.22 mL).
Purification by flash chromatography on silica gel (petroleum
ether/ethyl acetate 9:1 to 7:3) gave compound 25c (29.6 mg,
81%). nmax (CCl4)/cmꢀ1 2927, 2855, 1683, 1642, 1558, 1550. dH
(400 MHz, CDCl3) 4.20 (dd, J 11.5, 8.4, 1H), 4.00 (dd, J 11.5,
3.9, 1H), 3.42 (br s, 4H), 3.35 (m, 1H), 2.42 (m, 2H), 2.28 (2s,
3H), 2.07 (m, 1H), 1.90 (m, 1H), 1.63 (br s, 6H). dC (100.6 MHz,
CDCl3) 168.9 (CO), 118.7 (CN), 55.6 (CH2), 48.0 (2CH2), 34.7
(CH), 28.1 (CH2), 24.8 (3CH2), 23.5 (CH2), 22.3 (CH3), 13.9
(CH2). m/z (HR-EIþ) calc. for C17H20F2N4O 334.1605, found
334.1608.
Notes: even with a high number of scans, the C-F carbons
were not visible in the 13C NMR spectra.
1
The H NMR N-Ac signals of derivatives 25a–f and 25i
appear as two singlets because of the restricted rotation of the
amide bond on the NMR timescale. They are therefore described
as two singlets (2s).
3-(1-Acetyl-4,7-difluoro-6-morpholino-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25d)
Following method B, the reaction was carried out using
trifluoroazaindoline 23a (25 mg, 0.09 mmol, 1.0 equiv.) and
morpholine (15 mL, 0.20 mmol, 2.2 equiv.) in DMF (0.20 mL).
Purification by flash chromatography on silica gel (petroleum
ether/ethyl acetate 5:5 to 3:7) gave compound 25d (25.5 mg,
81%). nmax (CCl4)/cmꢀ1 2827, 2857, 1686, 1641, 1445, 1371. dH
(400 MHz, CDCl3) 4.28 (dd, J 11.4, 8.5, 1H), 4.06 (dd, J 11.4,
4.0, 1H), 3.84 (m, 4 H), 3.50 (m, 5H), 2.48 (m, 2H), 2.34 (2s,
3H), 2.14 (m, 1H), 1.96 (m, 1H). dC (100.6 MHz, CDCl3) 168.9
(CO), 118.7 (CN), 66.6 (2CH2), 56.6 (CH2), 48.0 (2CH2), 35.8
(CH), 28.9 (CH2), 23.3 (CH3), 14.9 (CH2). m/z (HR-EIþ) calc.
for C16H18F2N4O2 336.1398, found 336.1403.
3-(1-Acetyl-4,6,7-trifluoro-2,3-dihydro-1H-pyrrolo[3,2-c]
pyridin-3-yl)propanenitrile (23a)
Following the general procedure for the radical cyclization, the
reaction was carried out using xanthate 22a (3.19 g, 7.79 mmol,
1.0 equiv.) in n-amyl acetate (120 mL) and di-tert-butylperoxide
(7.13 mL, 39 mmol, 5.0 equiv.). Purification by flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate, 1:1 to 3:7)
yielded trifluoroazaindoline 23a (1.05 g, 50%).
3-(1-Acetyl-4,7-difluoro-6-(2-hydroxyethylamino)-2,3-
dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25a)
Following method B, the reaction was carried out using tri-
fluoroazaindoline 23a (31 mg, 0.12 mmol, 1.0 equiv.) and eth-
anolamine (21 mL, 0.3 mmol, 3.0 equiv.) in DMF (0.24 mL). The
reaction required 3 h to go to completion. Purification by flash
chromatography on silica gel (petroleum ether/ethyl acetate 9:1
to 0:10) gave compound 25a (10 mg, 28%). nmax (CCl4)/cmꢀ1
2927, 2855, 1644, 1558, 1554, 1550, 1466. dH (400 MHz,
CDCl3) 5.25 (s, 1H), 4.20 (dd, J 11.4, 8.5, 1H), 3.98 (dd, J 11.4,
4.0, 1H), 3.83 (t, J 4.9, 2H), 3.61 (m, 2H), 3.40 (m, 1H), 2. 43 (m,
2H), 2.31 (2s, 3H), 2.09 (m, 1H), 1.91 (m, 1H). dC (100.6 MHz,
CDCl3) 168.9 (CO), 118.7 (CN), 62.3 (CH2), 56.3 (CH2), 44.0
(CH2), 35.7 (CH), 29.2 (CH2), 23.5 (CH3), 14.9 (CH2). m/z
(HR-EIþ) calc. for C14H16F2N4O2 310.1241, found 310.1244.
3-(1-Acetyl-4,7-difluoro-6-(pyrrolidin-1-yl)-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25e)
Following method B, the reaction was carried out using
trifluoroazaindoline 23a (30 mg, 0.11 mmol, 1.0 equiv.) and pyr-
rolidine (28 mL, 0.33 mmol, 3.0 equiv.) in DMF (0.22 mL). The
reaction was stirred at room temperature and was complete after
3 h. Purification by flash chromatography on silica gel (petroleum
ether/ethyl acetate 8:2 to 6:4) gave difluoroazaindoline 25e
(33.2 mg, 94%). nmax (CCl4)/cmꢀ1 2974, 2952, 2876, 2251, 1681,
1643. dH (400MHz, CDCl3) 4.23 (dd, J 11.4, 8.3, 1H), 4.04 (dd, J
11.4, 3.8, 1H), 3.64 (m, 4H), 3.37 (m, 1H), 2.46 (m, 2H), 2.33 (2s,
3H), 2.09 (m, 1H), 1.97 (m, 5H). dC (100.6 MHz, CDCl3) 168.9
(CO), 118.7 (CN), 56.6 (CH2), 48.8 (2CH2), 35.8 (CH), 29.3
(CH2), 25.3 (2CH2), 23.3 (CH3), 14.9 (CH2). m/z (HR-EIþ) calc.
for C16H18F2N4O 320.1449, found 320.1455.
3-(1-Acetyl-6-(aziridin-1-yl)-4,7-difluoro-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25b)
3-(1-Acetyl-6-(dimethylamino)-4,7-difluoro-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25f)
Following method A, the reaction was carried out using tri-
fluoroazaindoline 23a (54 mg, 0.20 mmol, 1.0 equiv.) and
cyclopropylamine (30 mL, 0.40 mmol, 2.2 equiv.) in DMF
(0.4 mL). The reaction was complete after 3 h at 508C. Purifi-
cation by flash chromatography on silica gel (petroleum ether/
Following method B, the reaction was carried out using
trifluoroazaindoline 23a (30 mg, 0.11 mmol, 1.0 equiv.) and
dimethylamine (40% in water, 42 mL, 0.33 mmol, 3.0 equiv.) in

RESEARCH FRONT
Fluoroazaindolines
423
DMF (0.22 mL). Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 7:3 to 6:4) yielded difluoro-
azaindoline 25f (27.5 mg, 84%). nmax (CCl4)/cmꢀ1 2928, 2856,
2252, 1683, 1644. dH (400 MHz, CDCl3) 4.25 (dd, J 11.4, 8.3,
1H), 4.06 (dd, J 11.4, 3.9, 1H), 3.39 (m, 1H), 3.13 (d, J 2.6, 6H),
2.47 (m, 2H), 2.34 (2s, 3H), 2.11 (m, 1H), 1.95 (m, 1H). dC
(100.6 MHz, CDCl3) 168.9 (CO), 118.7 (CN), 55.7 (CH2), 40.2
(2CH3), 35.8 (CH), 29.2 (CH2), 23.2 (CH3), 14.9 (CH2). m/z
(HR-EIþ) calc. for C14H16F2N4O 294.1292, found 294.1285.
3.4 mmol, 3.6 equiv.). The reaction mixture was stirred at room
temperature until disappearance of the starting material. Water
and ethyl acetate were added and the aqueous layer was
extracted twice. The organic layer was dried (MgSO4), filtered,
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography on silica gel
(dichloromethane/methanol, 99:1 to 92:2) to yield the corre-
sponding unprotected fluoroazaindoline 25j (205 mg, 97%).
n
max (CCl4)/cmꢀ1 2927, 2855, 1644, 1466, 1377, 1260, 1096. dH
(400 MHz, CDCl3) 4.77 (s, 1H), 4.05 (m, 1H), 3.64 (m, 2H), 2.45
(t, J 7.3, 2H), 2.18 (m, 1H), 2.00 (m, 1H). dC (100.6 MHz,
CDCl3) 118.7 (CN), 54.3 (CH2), 37.7 (CH), 29.1 (CH2), 14.8
(CH2). m/z (HR-EIþ) calc. for C10H8N3F3 227.0670, found
227.0666.
3-(4,7-Difluoro-6-(1H-imidazol-1-yl)-2,3-dihydro-1H-
pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25g)
Following method C, the reaction was carried out using tri-
fluoroazaindoline 23a (50 mg, 0.19 mmol, 1.0 equiv.), imidaz-
ole (39 mg, 0.57 mmol, 3.0 equiv.) and NaH (60% suspension in
oil, 22.8 mg, 0.57 mmol, 3.0 equiv.) in DMF (0.8 mL). The
reaction was stirred at room temperature and was complete after
3 h. Purified by flash chromatography on silica gel (ethyl ace-
tate) gave compound 25g (30.3 mg, 58%). nmax (CCl4)/cmꢀ1
2962, 1642, 1544, 1488. dH (400 MHz, CDCl3) 8.24 (s, 1H), 7.63
(s, 1H), 7.14 (s, 1H), 5.28 (s, 1H), 4.06 (t, J 9.2, 1H), 3.65
(m, 2H), 2.46 (t, J 7.3, 2H), 2.20 (m, 1H), 2.02 (m, 1H). dC
(100.6 MHz, CDCl3) 136.4 (CH), 129.6 (CH), 117.6 (CH),
118.9 (CN), 54.1 (CH2), 38.1 (CH), 29.2 (CH2), 14.9 (CH2). m/z
(HR-EIþ) calc. for C13H11F2N5 275.0983, found 275.0990.
3-(4,6,7-Trifluoro-1H-pyrrolo[3,2-c]pyridin-3-yl)
propanenitrile (26)
IBX (1.20 g, 4.3 mmol, 5.0 equiv.) was dissolved in DMSO
(10.0 mL) and vigorously stirred for 30 min. Trifluoroazaindo-
line 25j (195 mg, 0.86 mmol, 1.0 equiv.) in DMSO (3.0 mL) was
then added and the mixture was stirred at 508C for 24 h. Water
was added (15 mL) and the mixture was stirred for two hours.
Filtration through a pad of Celite gave a filtrate, which was
extracted with ethyl acetate. The organic layer was washed with
brine, dried (MgSO4) and the solvent was removed under
reduced pressure. Purification by flash chromatography on silica
gel (dichloromethane/methanol, 98:2 to 96:4) gave the corre-
sponding azaindole 26 (97 mg, 50%). nmax (CCl4)/cmꢀ1 3236,
1642, 1558, 1541, 1504, 1373. dH (400 MHz, DMSO-d6) 12.65
(s, 1H), 7.59 (s, 1H), 3.09 (t, J 7.0, 2H), 2.92 (t, J 7.0, 2H). dC
(100.6 MHz, DMSO-d6) 127.4 (C), 120.1 (CH), 112.2 (CN),
21.0 (CH2), 17.9 (CH2). m/z (HR-EIþ) calc. for C10H6F3N3
225.0514, found 225.0514.
3-(4,7-Difluoro-6-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]
pyridin-3-yl)propanenitrile (25h)
Following method C, the reaction was carried out using tri-
fluoroazaindoline 23a (34 mg, 0.12 mmol, 1.0 equiv.), phenol
(64 mL, 0.72 mmol, 6.0 equiv.) and NaH (60% suspension in oil,
28.8 mg, 0.72 mmol, 6.0 equiv.) in DMF (0.5 mL). Purification
by chromatography on silica gel (petroleum ether/ethyl acetate
7:3 to 6:4) gave compound 25h (21.9 mg, 60%). nmax (CCl4)/
cmꢀ1 3442, 2930, 1655, 1550, 1546, 1542, 1455. dH (400 MHz,
CDCl3) 7.37 (t, J 7.9, 2H), 7.18 (t, J 7.4, 1H), 7.13 (d, J 7.7, 2H),
4.60 (s, 1H), 3.97 (t, J 8.5, 1H), 3.56 (m, 2H), 2.43 (t, J 7.4, 2H),
2.14 (m, 1H), 1.97 (m, 1H). dC (100.6 MHz, CDCl3) 129.4
(C2H), 124.7 (CH), 120.4 (2CH), 118.9 (CN), 54.2 (CH2),
37.8 (CH), 29.2 (CH2), 14.8 (CH2). m/z (HR-EIþ) calc. for
C16H13F2N3O 301.1027, found 301.1029.
3-(4,7-Difluoro-6-morpholino-2,3-dihydro-1H-pyrrolo
[3,2-c]pyridin-3-yl)propanenitrile (27)
Following method C, the reaction was carried out using tri-
fluoroazaindoline 23a (100 mg, 0.37 mmol, 1.0 equiv.) and
morpholine (70 mL, 0.81 mmol, 2.2 equiv.) in DMF (0.8 mL).
After the usual workup, the residue was dissolved in methanol
(4 mL) and potassium carbonate (270 mg, 1.90 mmol,
5.0 equiv.) was added. The reaction was stirred at room tem-
perature and monitored by TLC. Water and ethyl acetate were
added and the aqueous layer was extracted twice. The organic
layer was dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate 5:5
to 3:7) to give compound 27 (75.7 mg, 69%). nmax (CCl4)/cmꢀ1
2927, 2856, 1654, 1483. dH (400 MHz, CDCl3) 4.36 (s, 1H), 3.96
(td, J 9.0, 1.2, 1H), 3.83 (t, J 4.4, 4H), 3.60 (m, 1H), 3.53 (m, 1H),
3.47 (dd, J 5.6, 3.3, 4H), 2.48 (t, J 7.4, 2H), 2.17 (m, 1H), 2.02
(m, 1H). dC (100.6 MHz, CDCl3) 119.1 (CN), 66.8 (2CH2), 54.1
(CH2), 44.9 (2CH2), 37.9 (CH), 29.5 (CH2), 14.8 (CH2). m/z
(HR-EIþ) calc. for C14H16F2N4O 294.1292, found 294.1300.
3-(1-Acetyl-4,7-difluoro-6-(phenylthio)-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridin-3-yl)propanenitrile (25i)
Following method C, the reaction was carried out using tri-
fluoroazaindoline 23a (35 mg, 0.13 mmol, 1.0 equiv.), thiophe-
nol (40 mL, 0.39 mmol, 3.0 equiv.) and NaH (60% suspension in
oil, 15.6 mg, 0.39 mmol, 3.0 equiv.) in DMF (0.5 mL). Purifi-
cation by flash chromatography on silica gel (petroleum ether/
ethyl acetate 9:1 to 6:4) gave compound 25i (25 mg, 61%). nmax
(CCl4)/cmꢀ1 3065, 2930, 2251, 1687, 1623, 1557, 1554, 1452,
1406, 1372, 1322, 1298. dH (400 MHz, CDCl3) 7.55 (dd, J 6.5,
3.0, 2H), 7.42 (d, J 2.0, 1H), 7.41 (m, 2H), 4.28 (dd, J 11.6, 8.8,
1H), 4.04 (dd, J 11.6, 4.4, 1H), 3.45 (m, 1H), 2.42 (m, 2H), 2.34
(2s, 3H), 2.12 (m, 1H), 1.91 (m, 1H). dC (100.6 MHz, CDCl3)
168.9 (CO), 135.2 (2CH), 129.3 (2CH), 129.4 (CH), 118.5 (CN),
56.2 (CH2), 36.1 (CH), 28.7 (CH2), 23.5 (CH3), 14.9 (CH2). m/z
(HR-EIþ) calc. for C18H15F2N3OS 359.0904, found 359.0911.
3-(4,7-Difluoro-6-morpholino-1H-pyrrolo[3,2-c]pyridin-
3-yl)propanenitrile (28)
The reaction was carried out using azaindoline 27 (45 mg,
0.15 mmol, 1.0 equiv.) and IBX (85.3 mg, 0.30 mmol,
2.0 equiv.) in DMSO (1.6 mL). The reaction was stirred at room
temperature and was complete after 1 h. Water (2 mL) was
added and the mixture was stirred for 2 h at room temperature.
3-(2-Cyanoethyl)-4,6,7-trifluoro-2,3-dihydropyrrolo[3,2-c]
pyridine (25j)
To a solution of trifluoroazaindoline 23a (250 mg, 0.93 mmol,
1 equiv.) in methanol (1.0 mL), was added K2CO3 (600 mg,

RESEARCH FRONT
424
Y. Laot et al.
Filtration through a pad of Celite gave a filtrate, which was
extracted with ethyl acetate. The organic layer was washed
with brine, dried (MgSO4) and the solvent was removed under
reduced pressure. Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 7:3 to 6:4) gave azaindole 28
(13.7 mg, 31%). nmax (CCl4)/cmꢀ1 3478, 2927, 2856, 1711,
1655. dH (400 MHz, CDCl3) 8.49 (s, 1H), 7.03 (s, 1H), 3.85 (m,
4H), 3.41 (m, 4H), 3.09 (t, J 6.9, 2H), 2.73 (t, J 6.9, 2H). dC
(100.6 MHz, CDCl3) 118.3 (CN), 112.3 (CH), 111.4 (C), 65.9
(2CH2), 47.9 (2CH2), 21.1 (CH2), 18.1 (CH2). m/z (HR-EIþ)
calc. for C14H14F2N4O 292.1136, found 292.1141.
time the solvent was removed under reduced pressure. The
residue was dissolved in dichloromethane and water and the
aqueous layer was extracted twice. The organic layer was
washed with brine, dried (MgSO4), filtered and the solvent was
removed under reduced pressure. The crude amine was dis-
solved in acetic anhydride (15 mL) and one drop of concentrated
sulfuric acid was added. The mixture was stirred for 1 h at room
temperature and quenched with a saturated solution of NaHCO3.
Usual extraction with dichloromethane followed by purification
by flash chromatography on silica gel (petroleum ether/ethyl
acetate 9:1 to 7:3) yielded amide 34 contaminated with 15%
of N-allylacetamide. nmax (CCl4)/cmꢀ1 3051, 2989, 2304, 1695,
1643. dH (400 MHz, CDCl3) 5.75 (m, 1H), 5.09 (m, 2H), 4.27
(d, J 6.8, 2H), 1.90 (s, 3H). dC (100.6 MHz, CDCl3) 169.6 (C),
131.7 (CH2), 119.8 (CH), 50.5 (CH2), 21.6 (CH3). m/z (CI, NH3)
266 (MHþ).
O-Ethyl S-2-(Methyl(perfluoropyridin-4-yl)amino)-
2-oxoethyl Carbonodithioate (29)
Pentafluoropyridine (1.48 g, 8.79 mmol, 1.0 equiv.) was dis-
solved in ethanol (15 mL) and methylamine (33% in ethanol,
2.18 mL, 17.58 mmol, 2.0 equiv.) was added at 08C. The solu-
tion was stirred at room temperature for 20 min and the solvent
was removed. The residue was dissolved in dichloromethane
and water. The organic layer was washed with brine and dried
(MgSO4). Filtration and evaporation yielded an oil, which was
dissolved in 1,2-dichloroethane (15 mL). Bromoacetylbromide
(0.91 mL, 10.54 mmol, 1.2 equiv.) was added and the mixture
was stirred at 828C until consumption of the starting material.
The mixture was allowed to cool down to room temperature.
Water and dichloromethane were then added. Usual extraction
yielded an oil, which was diluted in acetone (15 mL). Potassium
O-ethyl carbonodithioate (1.55 g, 9.67 mmol, 1.1 equiv.) was
added portion-wise at 08C. The mixture was stirred for 15 min at
this temperature and the solvent was removed under reduced
pressure. Usual extraction followed by purification by flash
chromatography on silica gel (petroleum ether/ethyl acetate 7:3
to 1:1) gave xanthate 29 (2.50 g, 83%) as a mixture of rotamers.
S-4-Cyano-1-(N-(perfluorophenyl)acetamido)butan-
2-yl O-Ethyl Carbonodithioate (35)
A solution of olefin 34 (300 mg, 1.13 mmol, 1.0 equiv.) and
S-cyanomethyl O-ethyl carbonodithioate (273 mg, 1.69 mmol,
1.5 equiv.) in ethyl acetate (1.1 mL) was refluxed for 10 min
under a nitrogen atmosphere. Dilauroylperoxide (20 mg,
0.056 mmol, 0.05 equiv.) was then added and the solution was
stirred for 90 min. The reaction needed an additional 5 mol% of
DLP to go to completion. The solvent was then removed under
reduced pressure and the residue was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate, 8:2 to
7:3) to yield xanthate 35 (381 mg, 79%). nmax (CCl4)/cmꢀ1
2970, 2624, 1704, 1638, 1464, 1384, 1264. dH (400 MHz,
CDCl3) 4.59 (q, J 7.1, 2H), 4.45 (dd, J 14.3, 9.3, 1H), 3.68 (m,
1H), 3.50 (dd, J 14.3, 4.7, 1H), 2.63 (m, 1H), 2.53 (m, 1H), 2.26
(m, 1H), 2.04 (m, 1H), 1.95 (s, 3H), 1.38 (t, J 7.1, 3H). dC
(100.6 MHz, CDCl3) 212.0 (C), 170.5 (C), 118.4 (C), 70.8
(CH2), 49.4 (CH2), 48.5 (CH), 26.6 (CH2), 21.4 (CH3), 15.1
(CH2), 13.6 (CH3). m/z (HR-EIþ) calc. for C16H15F5N2O2S2
426.0495, found 426.0499.
n
max (CCl4)/cmꢀ1 1693, 1638, 1476, 1430, 1350. dH (400 MHz,
CDCl3) 4.58 (br s, 2H), 4.38–3.30 (m, 2H), 1.37 (br s, 3H).
dC (100.6 MHz, CDCl3) 212.6 (C), 166.1 (C), 70.99 (CH2),
38.2 (CH2), 36.4 (CH3), 13.5 (CH3). m/z (HR-EIþ) calc. for
C11H10O2N2F4S2 342.0120, found 342.0125.
3-(1-Acetyl-4,5,6,7-tetrafluoroindolin-3-yl)
4,6,7-Trifluoro-1-methyl-1H-pyrrolo[3,2-c]pyridin-
2(3H)-one (33)
propanenitrile (36)
Following the general procedure for the radical cyclization, the
reaction was carried out using a solution of xanthate 35 (201 mg,
0.47 mmol, 1.0 equiv.) in n-amylacetate (7.1 mL) and di-tert-
butylperoxide (0.72 mL, 2.35 mmol, 5.0 equiv.) Purification by
flash chromatography on silica gel (petroleum ether/ethyl ace-
tate, 8:2 to 6:4) yielded tetrafluoroindoline 36 in a somewhat
impure state and in 23% (NMR yield). IR (CCl4): nmax 2986,
1819, 1698, 1725, 1694, 1633, 1559, 1372, 1295. dH (400 MHz,
CDCl3) 4.22 (dd, J 11.4, 8.1, 1H), 4.10 (dd, J 10.6, 2.7, 1H), 3.56
(m, 1H), 2.45 (m, 2H), 2.29 (s, 3H), 2.12 (m, 1H), 1.96 (m, 1H).
dC (100.6 MHz, CDCl3) 169.5 (CO), 118.4 (CN), 55.7 (CH2),
37.8 (CH), 28.5 (CH2), 22.8 (CH3), 15.0 (CH2). m/z (HR-EIþ)
calc. for C13H10 ON2F4 286.0729, found 286.0735.
Xanthate 29 (500 mg, 2.47 mmol, 1.0 equiv.) was dissolved in
o-dichlorobenzene (18.5 mL). The solution was stirred at reflux
under a nitrogen atmosphere for 15 min. A degassed solution of
di-tert-butylperoxide (1.35 mL, 7.41 mmol, 3.0 equiv.) in o-di-
chlorobenzene (18.5 mL) was added dropwise under reflux in
90 min. Once the addition was finished, the solution was stirred
for an additional hour at reflux and allowed to cool down to room
temperature. The solution was eluted on a silica gel column with
petroleum ether (to remove the solvent) and then with the ap-
propriate solvent system (petroleum ether/ethyl acetate, 7:3 to
1:1) to yield azaoxindole 33 in a somewhat impure state and in a
low yield (o15%). nmax (CCl4)/cmꢀ1 1748, 1645, 1476, 1283. dH
(400 MHz, CDCl3) 3.56 (s, 2H), 3.44 (s, 3H). dC (100.6 MHz,
CDCl3) 173.2 (C, C(O)), 31.5 (CH2), 28.5 (CH3). m/z (CI, NH3)
203 (MþHþ).
Acknowledgements
This paper is respectfully dedicated to the memory of Professor Athelstan
L. J. Beckwith. L.P. and N.D.M.T. thank Laboratoires Servier and Ecole
Polytechnique respectively for a studentship.
N-Allyl-N-(perfluorophenyl)acetamide (34)
To a cold (08C) solution of perfluorobenzene (1.17 g,
6.28 mmol, 1.0 equiv.) in ethanol (13 mL) was added methyl-
amine (33% in ethanol, 1.56 mL, 12.56 mmol, 2.0 equiv.). The
mixture was stirred for 24 h at room temperature after which
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