Synthesis of 4-, 5- and 6-benzoylated 7-azaindoles

Article abstract of DOI:10.1055/s-2008-1067103

Efficient syntheses of 4-, 5- and 6-benzoyl-7-azaindoles are described. Two strategies were developed: i) formation of 4-lithio and 5-lithio-7-azaindole and reaction with aldehydes and ii) organomagnesium addition to 6-cyano-7-azaindole. Both methods shou

Full text of DOI:10.1055/s-2008-1067103

PAPER
2049
Synthesis of 4-, 5- and 6-Benzoylated 7-Azaindoles
Synthesis of 4-,
5
h
-
and 6-Benz
r
oylate
d
i
7-Azain
s
doles telle Pillard, Carine Ekambomé Bassène, Franck Suzenet,* Gérald Guillaumet
Institut de Chimie Organique et Analytique (I.C.O.A.), UMR-CNRS 6005, FR CNRS 2708, Université d'Orléans, Rue de Chartres,
BP 6759, 45067 Orléans Cedex 02, France
Fax +33(2)38417281; E-mail: gerald.guillaumet@univ-orleans.fr
Received 11 January 2008; revised 28 March 2008
RMgX
Abstract: Efficient syntheses of 4-, 5- and 6-benzoyl-7-azaindoles
are described. Two strategies were developed: i) formation of 4-
lithio and 5-lithio-7-azaindole and reaction with aldehydes and ii)
organomagnesium addition to 6-cyano-7-azaindole. Both methods
should allow the introduction of a diverse range of acyl substituents.
R
N
N
N
N
H
H
NC
N
N
H
O
1
4
Scheme 1
Key words: 7-azaindole, acylation, 6-cyano-7-azaindole, fused-
ring system, lithium–halogen exchange
(b)
88%
(a)
7-Azaindole derivatives may be considered as useful in-
dole bioisosteres in medicinal chemistry. An increasing
number of pharmaceutically active compounds with ap-
plication in various therapeutic areas contain the 7-aza-
indole (1-H-pyrrolo[2,3-b]pyridine) pharmacophore.1
Functionalisation at C-2 and C-3 of the pyrrole moiety is
well documented in the literature.2 For example, the direct
Friedel–Crafts acylation is known to preferentially take
place at the C-3 position of the azaindole core.3 However,
the regioselective functionalisation of the electron-defi-
cient pyridine ring of 7-azaindole remains a major chal-
lenge. A few approaches involve pyrrolo annelation into a
preformed pyridine ring1,2 and, more recently, some
progress has been achieved starting from the N-oxide de-
rivative.4 In the course of our own program in medicinal
chemistry, we required an efficient synthesis of 4-, 5- and
6-acylated 7-azaindole (Figure 1). In this paper, we wish
to describe efficient methods with which to prepare acy-
lated azaindole templates 1–3 (Figure 1, exemplified with
R = phenyl).
N
N
O–
N
N
H
74%
+
H
N
NC
N
H
5
4
(c)
N
N
84%
H
O
6
Scheme 2 Reagents and conditions: (a) m-CPBA, EtOAc, r.t., 1 h;
(b) TMSCN, Et3N, MeCN, reflux, 6 days; (c) (i) PhMgBr, TMSCl,
THF, r.t., 15 h; (ii) H2O.
aged the synthesis of azaindole 1 by addition of an orga-
nomagnesium compound on the cyano precursor 4
(Scheme 1).
The only known cyanation of 7-azaindole was performed
at the 6-position by the treatment of its N-oxide with tri-
methylsilyl cyanide in the presence of benzoyl chloride.5,6
The resulting 1-benzoyl-6-cyano-7-azaindole was ob-
tained with low yield (39%) and the benzoyl group had to
be removed by basic treatment.7 Thus, the development of
an improved cyanation of the N-oxide 58 was undertaken.
In reference to the pyridine chemistry, however, we found
that treatment of compound 5 with trimethylsilanecarbo-
nitrile and dimethylcarbamyl chloride in dichloromethane,9
did not lead to the desired product. On the other hand, the
one-step conversion of pyridine N-oxide into the a-cyano
pyridine reported by Vorbrüggen and Krolikiewicz,10
prompted us to evaluate the cyanation of the unprotected
N-oxide 5 with trimethylsilyl cyanide (TMSCN) in aceto-
nitrile in the presence of triethylamine11 (Scheme 2). The
expected 6-cyano-7-azaindole (4) was isolated in an ex-
cellent 88% yield. Although theoretically only three
equivalents of trimethylsilyl cyanide are needed,10 less
than six equivalents led to lower yields. When phenyl-
magnesium bromide was added to compound 4 in the
presence of trimethylsilyl chloride (TMSCl), the desired
6-Substituted 7-azaindoles have generally been prepared
through ring closure of pyridine derivatives including the
functional group.1,2 Halogen and thiocyanato groups have
been introduced onto position 6 of 7-azaindole via a
Reissert–Henze salt. To permit the introduction of a wide
range of acyl groups onto the 7-azaindole core, we envis-
R
O
O
R
R
N
N
N
H
N
N
N
H
H
O
2
3
1
Figure 1 Target molecules
SYNTHESIS 2008, No. 13, pp 2049–2054
x
x.
x
x
.
2
0
0
8
Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067103; Art ID: T00508SS
© Georg Thieme Verlag Stuttgart · New York

2050
C. Pillard et al.
PAPER
I
OH
N
Br
I
O
(a)
(b)
Br
R
R
70%
92%
N
NHPv
N
NHPv
N
NHPv
N
N
N
N
H
H
N
H
9
10
3 (4-Ac)
2 (5-Ac)
7 (4-Br)
8 (5-Br)
Scheme 5 Reagents and conditions: (a) (i) n-BuLi, THF, –40 °C to
–10 °C, 4 h; (ii) I2, THF, –78 °C to r.t., 1 h; (b) Br2, DMF, r.t., 24 h.
Scheme 3
performed on the iodine atom of 10 with a mixture (84:16)
of ethoxyvinylstannanes 11 and 1214 in the presence of
dichlorobis(triphenylphosphine)-palladium and tetraethyl-
ammonium chloride in acetonitrile under reflux.15 The re-
sulting enol ethers 13 and 14 were directly heated in
sulfuric acid (10%) to provide the desired azaindole 8 and
the ketone 15. In order to facilitate the purification by
chromatography on silica gel, ketone 15 was reduced by
treating the crude mixture with sodium borohydride.
Thus, the resulting alcohol 16 was easily removed and 5-
bromo-7-azaindole (8) was obtained in 45% yield over
three steps (Scheme 6). This procedure was performed on
a large scale (10 g) and required only one recrystallization
and one purification by chromatography on silica gel from
2-(pivaloylamino)pyridine.
Br
N
ref. 4
N
N
N
H
H
7
Scheme 4
6-benzoyl-7-azaindole (6) was obtained in 84% yield
(overall yield 55% in 3 steps from 7-azaindole).
To obtain analogues 2 and 3 acylated at positions C-5 and
C-4, respectively, we envisaged a lithium–halogen ex-
change approach followed by treatment with an aldehyde
as electrophile and further oxidation of the intermediate
alcohol (Scheme 3).
An initial attempt to affect the metal–halogen exchange of
5-bromo-7-azaindole (8) with three equivalents of tert-
butyllithium was unsuccessful. Rapoport and co-
workers16 have demonstrated that, because the metal–
halogen exchange was so rapid, it might effectively com-
pete with abstraction of the indole NH. In order to prevent
this problem, methyllithium was first used to remove the
acidic pyrrole proton on 7 and 8.17 After complete depro-
tonation, two equivalents of tert-butyllithium were added
Synthesis of the required 4-bromo-7-azaindole (7) was
planned from commercially available 7-azaindole using a
known procedure (Scheme 4).4
In the case of 5-bromo-7-azaindole (8), an alternative ap-
proach to the known synthesis described by Guillaumet
and co-workers12 from 7-azaindole was investigated. The
strategy consisted of initial bromination of the pyridine,
followed by pyrrole ring annelation.
The m-bromopyridine intermediate 10 was prepared as to promote the bromine–lithium exchange. Benzaldehyde
shown in Scheme 5. The ortho-metallation of commer- was then added to provide alcohols 17 and 18 in 73% and
cially available 2-(pivaloylamino)pyridine provided the 90% yield, respectively. Finally, oxidation of the benzylic
iodo derivate 913 in 70% yield, which was brominated in alcohols was carried out by tert-butyl hydroperoxide in
dimethylformamide to give the desired 5-bromo-3-iodo- the presence of catalytic amounts of chromium(VI) ox-
pyridine (10). Stille cross-coupling was chemoselectively
OEt
OEt
Br
Br
I
Br
SnBu3
OEt
OEt
NHPv
(a)
+
+
+
N
NHPv
SnBu3
N
N
NHPv
(84:16)
10
12
13
14
11
O
Br
Br
(b)
+
13
+
14
N
H
N
N
NH2
8
15
OH
Br
(c)
8
+
8
+
15
N
NH2
16
8% in 3 steps
45% in 3 steps
Scheme 6 Reagents and conditions: (a) PdCl2(PPh3)2, Et4NCl, MeCN, reflux, 20 h; (b) H2SO4 (10%), reflux, 5 h; (c) NaBH4, MeOH, r.t., 24 h.
Synthesis 2008, No. 13, 2049–2054 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-, 5- and 6-Benzoylated 7-Azaindoles
2051
ide,18 to afford the desired 4- and 5-benzoyl-7-azaindoles
19 and 20 (Scheme 7).
Chemical shifts (d) are reported in parts per million (ppm) and the
coupling constants (J) are reported in Hertz (Hz). IR spectra were
recorded on a Perkin–Elmer PARAGON 1000 PC spectrophotome-
ter. HRMS (ESI-TOF) were performed on a Micromass LC TOF
spectrometer.
X
R
R
(a)
(b)
N
N
1H-Pyrrolo[2,3-b]pyridine-7-oxide (5)
N
N
N
N
H
H
H
Prepared from commercially available 7-azaindole according to the
procedure described by Benoît, Gringas and Soundara.8
19 R = 4-Bz 53%
20 R = 5-Bz 69%
7
8
X = 4-Br
X = 5-Br
17 R = 4-CH(OH)Ph 73%
18 R = 5-CH(OH)Ph 90%
1H-Pyrrolo[2,3-b]pyridine-6-carbonitrile (4)
Scheme 7 Reagents and conditions: (a) (i) MeLi (1 equiv), THF,
–78 °C, 20 min; (ii) t-BuLi (2 equiv), –78 °C, 15 min; (iii) PhCHO,
–78 °C to r.t., 16 h; (iv) H2O; (b) CrO3, t-BuOOH, CH2Cl2, r.t., 24 h.
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-7-oxide (5; 11.27
g, 84.02 mmol) in MeCN (450 mL) was added Et3N (29.3 mL,
210.05 mmol) and TMSCN (50 g, 504.12 mmol) in 5 portions. The
mixture was heated to reflux for 6 days then quenched with sat.
NaHCO3 (500 mL). The aqueous phase was extracted with CH2Cl2
(2 × 300 mL) and the combined organic layers were dried over
MgSO4, filtered and evaporated under reduced pressure to obtain 4.
The analytical data were in accordance with literature values.7
An alternative synthesis of compound 20 was studied us-
ing the metallation chemistry developed by L’Heureux19
on the protected 4-chloro-7-azaindole (21; Scheme 8).
Thus, ortho-metallation of 21 with sec-butyllithium in
tetrahydrofuran and treatment with benzaldehyde gave al-
cohol 22 in 93% yield. The success of this approach was
dependent on the selective reduction of the C–Cl in com-
parison to the benzylic alcohol function. Numerous at-
tempts under radical conditions, with zinc in acetic acid20
or Pd hydrogenation with H2 were ineffective or led to
mixtures of compounds. Finally, the use of Pd/C in the
presence of ammonium formiate in THF–water21 fur-
nished azaindole 23. Oxidation with MnO2 and removal
of the silyl group afforded the benzoyl derivative 20.
Yield: 10.6 g (88%); white solid; mp 177–178 °C.
IR (KBr): 3407, 2228, 1580, 1412 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.65 (d, J = 2.9 Hz, 1 H, H-3),
7.50 (d, J = 8.0 Hz, 1 H, H-5), 7.72 (d, J = 2.9 Hz, 1 H, H-2), 8.08
(d, J = 8.0 Hz, 1 H, H-4), 11.40 (br s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 101.8 (C-3), 118.8 (CN), 120.2 (C-
5), 123.9 (Cq), 124.6 (Cq), 129.6 (C-4), 130.2 (C-2), 148.4 (Cq).
Phenyl(1H-pyrrolo[2,3-b]pyridine-6-yl)methanone (6)
To a stirred solution of phenylmagnesium bromide (1 M in THF,
25.2 mL, 25.2 mmol) in THF (7 mL) was added a solution of 1H-
pyrrolo[2,3-b]pyridine-6-carbonitrile (4; 0.6 g, 4.2 mmol) and
TMSCl (1.07 mL, 8.4 mmol) in THF (7 mL). After stirring over-
night at r.t., the mixture was quenched with NH4Cl (2 N, 20 mL) and
acidified with aq HCl (10%) to pH 1. The resulting solution was
stirred for 2 h at r.t. and basified with concentred ammonia solution
to pH 9. The aqueous layer was extracted with CH2Cl2 (2 × 20 mL)
and the organic layers were dried over MgSO4, filtered and evapo-
rated. The crude product was purified by flash chromatography on
silica gel (CH2Cl2 then CH2Cl2–MeOH, 99:1) to obtain the title
compound.
In conclusion, we have prepared 6-cyano-7-azaindole (4)
and, after addition of phenylmagnesium bromide, 6-ben-
zoyl-7-azaindole (6) in good yield. We have also devel-
oped a new synthesis of 5-bromo-7-azaindole (8) through
a palladium-catalysed sequence. The efficient lithium–
halogen exchange allowed the formation of the 4- and 5-
benzoyl-7-azaindoles analogues. This methodology pro-
vides a powerful tool for the preparation of 4-, 5- and 6-
benzoylated 7-azaindoles.
Yield: 784 mg (84%); yellow solid; mp 172–174 °C.
IR (KBr): 3407, 1657 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.50 (d, J = 1.2 Hz, 1 H, H-3),
7.25 (t, J = 2.8 Hz, 1 H, H-2), 7.47–7.60 (m, 3 H, ArH), 7.85 (d,
J = 7.8 Hz, 1 H, H-5), 8.06 (m, 3 H, H-4 and ArH), 12.80 (br s, 1 H,
NH).
13C NMR (63 MHz, CDCl3): d = 100.4 (C-3), 118.4 (C-5), 123.9
(Cq), 128.5 (CHPh), 128.7 (C-4), 130.8 (CHPh), 131.0 (C-2), 132.8
(CHPh), 137.9 (Cq), 146.6 (Cq), 148.2 (Cq), 195.0 (CO).
All chemicals were obtained from Aldrich or Acros and used with-
out further purification. THF was distilled from sodium with ben-
zophenone as indicator under argon prior to use. Experiments were
performed under an anhydrous and oxygen-free argon atmosphere
except were otherwise specially indicated. For TLC, aluminium
sheets (Merck silca gel coated 60 F254) were used and the plates
were visualized with UV light. Merck silica gel 40–70 mm (230–400
mesh) was used for flash chromatography. Melting points were de-
termined on a Büchi apparatus and are uncorrected. 1H NMR (250
MHz) and 13C NMR (62.5 MHz) were recorded on a Bruker Avance
DPX250 spectrometer at 25 °C, using TMS as an internal standard.
HRMS: m/z [M + H]+ calcd for C14H11N2O: 223.0871; found:
223.0865.
Cl
N
Cl
O
R
R
(b)
(d)
(a)
Ph
93%
77%
88%
N
N
N
N
N
N
N
H
TIPS
TIPS
TIPS
21
22 R = CH(OH)Ph
23 R = CH(OH)Ph
24 R = Bz
20
(c)
68%
Scheme 8 Reagents and conditions: (a) (i) s-BuLi (2.2 equiv), THF, –78 °C; (ii) PhCHO, –78 °C to r.t., 16 h; (iii) H2O; (b) Pd/C, HCO2NH4,
THF–H2O, r.t., 28 h; (c) MnO2, toluene, reflux, 20 h; (d) TBAF, THF, r.t., 3 h.
Synthesis 2008, No. 13, 2049–2054 © Thieme Stuttgart · New York

2052
C. Pillard et al.
PAPER
N-(3-Iodopyridin-2-yl)-2,2-dimethylpropionamide (9)
H-6 trans), 8.27 (d, J = 2.1 Hz, 1 H, H-4 cis), 8.39 (d, J = 2.1 Hz,
1 H, H-6 cis).
To a stirred solution of n-BuLi (1.6 M in hexane, 210 mL, 337
mmol) was added dropwise at –40 °C a solution of 2,2-dimethyl-N-
pyridin-2-yl-propionamide (20 g, 112 mmol) in THF (70 mL). After
4 h of stirring at –10 °C, the mixture was cooled to –78 °C and a so-
lution of I2 (60 g, 236 mmol) in THF (80 mL) was added via a drop-
ping funnel. After 1 h, the reaction mixture was allowed to reach r.t.,
quenched with sat. NaHCO3 (100 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were dried over
MgSO4, filtered and evaporated. The crude product was recrystal-
lised (CH2Cl2–pentane) to give the title compound. The analytical
data were in accordance with literature values.13
N-5-Bromo-3-(1-ethoxyvinylpyridin-2-yl)-2,2-dimethylpropi-
onamide (14)
1H NMR (250 MHz, CDCl3): d = 1.35 (m, 12 H, CH3), 3.92 (q,
J = 7.0 Hz, 2 H, CH2), 4.48 (s, 2 H, CH2), 7.76 (d, J = 2.1 Hz, 1 H,
H-4), 7.95 (br s, 1 H, NH), 8.48 (d, J = 2.1 Hz, 1 H, H-6).
The mixture of enol ethers 13 and 14 was dissolved in aq H2SO4
(10%; 75 mL) and heated to reflux for 5 h. The reaction was basified
with NaOH to pH 9 and extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried over MgSO4, filtered and evap-
orated to obtain a mixture of azaindole 8 and ketone 15. To a solu-
tion of this crude mixture in MeOH (150 mL) was added,
portionwise, NaBH4 (0.360 mg, 9.5 mmol). The resulting solution
was stirred for 24 h at r.t. then quenched with H2O (15 mL). MeOH
was evaporated under reduced pressure and the residue was extract-
ed with CH2Cl2 (2 × 100 mL). The combined organic layers were
dried over MgSO4, filtered and evaporated to give the crude prod-
uct, which was purified by flash chromatography on silica gel (PE–
EtOAc–Et3N, 3:2:1 then CH2Cl2–MeOH, 9:1) to give the desired
product 8 and alcohol 16. The analytical data were in accordance
with literature values.12
Yield: 23.8 g (70%); white solid; mp 147–148 °C.
IR (KBr): 3298, 3044, 2974, 2934, 2874, 1670 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.37 (s, 9 H, 3 × CH3), 6.84 (dd,
J = 4.9, 7.8 Hz, 1 H, H-5), 7.92 (br s, 1 H, NH), 8.11 (dd, J = 1.5,
7.8 Hz, 1 H, H-4), 8.45 (dd, J = 1.5, 4.9 Hz, 1 H, H-6).
13C NMR (63 MHz, CDCl3): d = 27.5 (CH3), 40.1 (Cq), 88.2 (Cq),
121.7 (C-5), 147.9 (C-4), 148.3 (C-6), 151.1 (Cq), 176.0 (Cq).
N-(5-Bromo-3-iodopyridin-2-yl)-2,2-dimethylpropionamide
(10)
To a stirred solution of N-(3-iodopyridin-2-yl)-2,2-dimethylpropi-
onamide (9; 12 g, 39.5 mmol) in DMF (54 mL) was added Br2 (5.07
mL, 98.7 mmol) via a dropping funnel. After 24 h of stirring at r.t.,
the solvent was removed under reduced pressure. The resulting oil
was dissolved in CH2Cl2 (50 mL) and washed with Na2S2O3 solu-
tion (5%; 2 × 20 mL). The organic layer was dried over MgSO4, fil-
tered and evaporated to give 10.
5-Bromo-1H-pyrrolo[2,3-b]pyridine (8)
Yield: 231 mg (45% over 3 steps); white solid; mp 174–176 °C
IR (KBr): 3136 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.47 (d, J = 3.5 Hz, 1 H, H-3),
7.37 (d, J = 3.5 Hz, 1 H, H-2), 8.08 (d, J = 2.2 Hz, 1 H, H-4), 8.36
(d, J = 2.2 Hz, 1 H, H-6), 10.13 (br s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 100.6 (C-3), 111.7 (Cq), 122.2 (Cq),
126.8 (C-2), 131.3 (C-4), 143.2 (C-6), 147.1 (Cq).
Yield: 13.9 g (92%); white solid; mp 192–194 °C.
IR (KBr): 3298, 1670 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.36 (s, 9 H, 3 × CH3), 7.89 (br s,
1 H, NH), 8.22 (d, J = 2.1 Hz, 1 H, H-4), 8.48 (d, J = 2.1 Hz, 1 H,
H-6).
13C NMR (63 MHz, CDCl3): d = 27.6 (CH3), 40.3 (Cq), 88.1 (Cq),
115.8 (Cq), 149.2 (C-4), 149.3 (C-6), 149.9 (Cq), 176.0 (Cq).
HRMS: m/z [M + H]+ calcd for C10H1379BrIN2O: 382.9256; found:
382.9263.
1-(2-Amino-5-bromopyridin-3-yl)ethanol (16)
Yield: 40 mg (8% over 3 steps); mp 171–172 °C
IR (KBr): 3634, 3444, 3266–3158, 2970–2857, 1675, 1622 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.51 (d, J = 6.6 Hz, 3 H, CH3),
3.84 (br s, 1 H, OH), 4.24 (q, J = 6.6 Hz, 1 H, CHOH), 5.19 (br s,
2 H, NH2), 7.34 (d, J = 1.8 Hz, 1 H, H-4), 7.86 (d, J = 1.8 Hz, 1 H,
H-6).
13C NMR (63 MHz, CDCl3): d = 21.4 (CH3), 68.0 (CHOH), 107.7
4-Bromo-1H-pyrrolo[2,3-b]pyridine (7)
Prepared from commercially available 7-azaindole according to the
(Cq), 124.9 (Cq), 136.9 (C-4), 146.9 (C-6), 155.6 (Cq).
procedure described by Thibault and co-workers.4
HRMS: m/z [M + H]+ calcd for C7H1079BrN2O: 216.9976; found:
219.9984.
Preparation of Compound 8
A solution of pyridine 10 (1.0 g, 2.61 mmol), stannane mixture 11
and 12 (1.13 g, 3.13 mmol) and tetraethylammonium chloride
(0.433 g, 2.61 mmol) in MeCN (20 mL) was degassed 3 times with
Phenyl(1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (17)
To a stirred solution of azaindole 7 (0.780 g, 3.96 mmol) in THF (9
mL) was added dropwise at –78 °C, MeLi (1.4 M in Et2O, 4 mL,
5.54 mmol). The mixture was stirred for 20 min at –78 °C then t-
BuLi (1.5 M in pentane, 6.6 mL, 9.9 mmol) was added. After stir-
ring for 15 min at –78 °C, benzaldehyde (2 mL, 19.8 mmol) was
added slowly. The mixture was allowed to warm slowly to r.t.,
stirred for 2 h then quenched with sat. NaHCO3 (10 mL) and ex-
tracted with CH2Cl2 (3 × 10 mL). The organic layers were dried
over MgSO4, filtered and evaporated under reduced pressure. The
crude product was purified by flash chromatography (PE–EtOAc,
1:1) to obtain the title azaindole 17.
argon. Dichlorobis(triphenylphosphine)palladium (0.073 g,
4
mol%) was added and the mixture was heated to reflux for 20 h. Af-
ter cooling to r.t., sat. KF (10 mL) and EtOAc (10 mL) were added
and this mixture was vigorously stirred for 30 min to precipitate the
tin salts. After filtration through celite, the filtrate was extracted
with EtOAc (2 × 20 mL) and the combined organic layers were
dried over MgSO4, filtered and evaporated. The crude oil, which ap-
peared to be a mixture of 13 and 14, was used without purification.
N-5-Bromo-3-[(E/Z)-2-ethoxyvinylpyridin-2-yl]-2,2-dimethyl-
propionamide (13)
Yield: 0.648 g (73%); yellow solid; mp 68–69 °C.
IR (KBr): 1125, 1224, 3320 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 6.03 (br s, 2 H, CH and OH),
6.42 (d, J = 3.1 Hz, 1 H, H-3), 7.29–7.42 (m, 7 H, H-2, H-5 and
ArH), 8.17 (d, J = 5.0 Hz, 1 H, H-6), 11.50 (br s, 1 H, NH).
1H NMR (250 MHz, CDCl3): d = 1.32 (m, 24 H, CH3 cis and trans),
3.86 (q, J = 7.0 Hz, 2 H, CH2 trans), 4.02 (q, J = 7.0 Hz, 2 H, CH2
cis), 5.03 (d, J = 7.0 Hz, 1 H, CHenol cis), 5.54 (d, J = 12.8 Hz, 1 H,
CHenol trans), 6.36 (d, J = 7.0 Hz, 1 H, CHenol cis), 6.90 (d, J = 12.8
Hz, 1 H, CHenol trans), 7.71 (br s, 1 H, NH cis), 7.75 (d, J = 2.1 Hz,
1 H, H-4 trans), 7.93 (br s, 1 H, NH trans), 8.20 (d, J = 2.1 Hz, 1 H,
Synthesis 2008, No. 13, 2049–2054 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-, 5- and 6-Benzoylated 7-Azaindoles
2053
13C NMR (63 MHz, DMSO-d6): d = 72.4 (CHOH), 99.0 (C-3),
111.9 (C-5), 117.0 (Cq), 125.3 (C-2), 126.4 (CHPh), 126.9 (CHPh),
128.0 (CHPh), 142.5 (C-6), 144.5 (Cq), 145.7 (Cq), 148.7 (Cq).
HRMS: m/z [M + H]+ calcd for C14H13N2O: 225.1028; found:
225.1028.
Method B: To a stirred solution of ketone 24 (0.250 g, 0.66 mmol)
in THF (3 mL) under an argon atmosphere, was added TBAF (1M
in THF, 1.45 mL, 1.45 mmol). The mixture was stirred 3 h at r.t.
then quenched with H2O (10 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over MgSO4, filtered
and evaporated under reduced pressure. The crude product was pu-
rified by flash chromatography (PE–EtOAc, 6:4 then 5:5) to pro-
vide the desired ketone.
Phenyl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (18)
To a stirred solution of azaindole 8 (3 g, 15.23 mmol) in THF (100
mL) was added dropwise at –78 °C, MeLi (1.4 M in Et2O, 15.23
mL, 21.32 mmol). The mixture was stirred for 20 min at –78 °C
then t-BuLi (1.6 M in pentane, 25.4 mL, 38.07 mmol) was added.
After stirring for 15 min at –78 °C, benzaldehyde (6.2 mL, 60.92
mmol) was added slowly. The mixture was allowed to warm slowly
to r.t., stirred for 16 h then quenched with sat. NaHCO3 (100 mL)
and extracted with CH2Cl2 (3 × 100 mL). The organic layers were
dried over MgSO4, filtered and evaporated under reduced pressure.
The crude product was purified by flash chromatography (PE–
EtOAc, 6:4 then 5:5) to obtain the desired azaindole 18.
Yield: 130 mg (88%); white solid; mp 174 °C.
IR (KBr): 1659 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.64 (d, J = 3.4 Hz, 1 H, H-3),
7.50–7.63 (m, 4 H, H-2 and ArH), 7.84 (d, J = 7.7 Hz, 2 H, ArH),
8.46 (s, 1 H, H-4), 8.90 (s, 1 H, H-6), 11.70 (br s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 102.6 (C-3), 119.9 (Cq), 127.3 (C-
2 and Cq), 128.6 (CHPh), 130.1 (CHPh), 132.0 (C-4), 132.5 (CHPh),
138.3 (Cq), 145.5 (C-6), 150.4 (Cq), 196.0 (Cq).
HRMS: m/z [M + H]+ calcd for C14H11N2O: 223.0871; found:
223.0872.
Yield: 3.07 g (90%); beige solid; mp 154–155 °C.
IR (KBr): 1216, 3616 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.00 (s, 1 H, CHOH), 6.45 (d,
J = 3.4 Hz, 1 H, H-3), 7.27–7.45 (m, 6 H, H-2 and ArH), 7.93 (d,
J = 1.9 Hz, 1 H, H-4), 8.29 (d, J = 1.9 Hz, 1 H, H-6).
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (21)
Prepared according to the procedure described by Benoît, Gringas
and Soundara.8
13C NMR (63 MHz, CDCl3): d = 74.6 (CHOH), 101.0 (C-3), 120.4
(Cq), 125.9 (C-2 and Cq), 126.5 (CHPh), 127.6 (C-4), 127.7 (CHPh),
128.6 (CHPh), 142.1 (C-6), 144.0 (Cq), 147.7 (Cq).
HRMS: m/z [M + H]+ calcd for C14H13N2O: 225.1028; found:
225.1022.
(4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-
yl)phenylmethanol (22)
A round-bottom flask was evacuated and backfilled with argon. The
flask was charged with 4-chloro-7-azaindole (21; 1.5 g, 4.86 mmol)
and THF (50 mL) and the mixture was cooled to –78 °C. s-BuLi
(1.3 M in hexane–cyclohexane, 8.2 mL, 10.69 mmol) was added
dropwise and, after stirring for 30 min at –78 °C, benzaldehyde (1.3
mL, 12.15 mmol) was added rapidly. The mixture was stirred for 14
h at ambient temperature then sat. NH4Cl (40 mL) was added. After
extraction with CH2Cl2 (3 × 50 mL), the combined organic layers
were dried over MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by flash chromatography
(PE–EtOAc, 98:2) to obtain the desired azaindole 22.
Phenyl(1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (19)
To a stirred mixture of chromium(VI) oxide (15 mg, 0.15 mmol) in
CH2Cl2 (50 mL) was added, sequentially, commercial aq tert-butyl
hydroperoxide (70%; 1.6 mL, 11.6 mmol) and alcohol 17 (0.650 g,
2.9 mmol). After stirring for 24 h at r.t. under an air atmosphere, the
mixture was quenched with aq Na2S2O3 (5%; 50 mL) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were dried
over MgSO4, filtered and evaporated. The crude material was puri-
fied by flash chromatography (PE–EtOAc, 1:1) to give the desired
product 19.
Yield: 1.88 g (93%); colourless oil.
IR (NaCl): 758, 1216, 3620 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.03–1.12 (m, 18 H, CH3), 1.82
(sept, J = 7.6 Hz, 3 H, CH i-Pr), 2.67 (s, 1 H, OH), 6.35 (s, 1 H,
CHOH), 6.63 (d, J = 3.5 Hz, 1 H, H-3), 7.23–7.47 (m, 6 H, H-2 and
ArH), 8.33 (s, 1 H, H-6).
13C NMR (63 MHz, CDCl3): d = 12.3 (CH i-Pr), 18.2 (CH3 i-Pr),
71.9 (CHOH), 101.9 (C-3), 121.6 (Cq), 126.7 (CHPh), 127.6 (CHPh),
128.4 (Cq), 128.5 (CHPh), 132.3 (C-2), 133.5 (Cq), 142.7 (C-6),
142.8 (Cq), 153.6 (Cq).
Yield: 0.342 g (53%); yellow oil.
IR (NaCl): 1680, 1130 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.42 (d, J = 3.2 Hz, 1 H, H-3),
7.30 (d, J = 4.7 Hz, 1 H, H-5), 7.47–7.53 (m, 3 H, H-2 and ArH),
7.60 (t, J = 7.4 Hz, 1 H, ArH), 7.87 (d, J = 7.4 Hz, 2 H, ArH), 8.48
(d, J = 5.0 Hz, 1 H, H-6), 11.40 (br s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 101.4 (C-3), 116.5 (C-5), 119.0
(Cq), 127.6 (C-2), 128.6 (CHPh), 130.3 (CHPh), 133.3 (CHPh), 136.9
(Cq), 137.4 (Cq), 142.0 (C-6), 150.1 (Cq), 196.3 (Cq).
HRMS: m/z [M + H]+ calcd for C23H32N2O28Si35Cl: 415.1972;
found: 415.1985.
HRMS: m/z [M + H]+ calcd for C14H11N2O: 223.0871; found:
223.0884.
Phenyl(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-
yl)methanol (23)
To a solution of 22 (0.580 g, 1.40 mmol) in THF (24 mL), was add-
ed ammonium formate (0.325 g, 5.04 mmol), H2O (8 mL) and Pd/C
(5%; 0.232 g). The mixture was stirred under an argon atmosphere
for 28 h at r.t., then filtered and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried over MgSO4, filtered and
evaporated under reduced pressure. The crude product was purified
by flash chromatography (PE–CH2Cl2, 5:5 then 0:10) to obtain the
azaindole 23.
Phenyl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (20)
Method A: To a stirred mixture of chromium(VI) oxide (31 mg, 0.31
mmol) in CH2Cl2 (140 mL) was added, sequentially, commercial aq
tert-butyl hydroperoxide (70%; 3.43 mL, 24.99 mmol) and alcohol
18 (1.4 g, 6.25 mmol). After stirring for 21 h at r.t. under an air at-
mosphere, the mixture was quenched with aq Na2S2O3 (5%; 100
mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried over MgSO4, filtered and evaporated. The crude
material was purified by flash chromatography (PE–EtOAc, 6:4
then 5:5) to give the desired product 20.
Yield: 410 mg (77%); colourless oil.
IR (NaCl): 1021, 2868, 3610 cm–1.
Yield: 0.958 g (69%); white solid; mp 174–175 °C.
Synthesis 2008, No. 13, 2049–2054 © Thieme Stuttgart · New York

2054
C. Pillard et al.
PAPER
(2) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y.
1H NMR (250 MHz, CDCl3): d = 1.11 (d, J = 7.5 Hz, 18 H, CH3 i-
Pr), 1.84 (sept, J = 7.5 Hz, 3 H, CH i-Pr), 2.28 (br s, 1 H, OH), 5.98
(s, 1 H, CHOH), 6.49 (d, J = 3.5 Hz, 1 H, H-3), 7.25–7.47 (m, 6 H,
H-2 and ArH), 7.82 (d, J = 2.0 Hz, 1 H, H-4), 8.28 (d, J = 2.0 Hz,
1 H, H-8).
13C NMR (63 MHz, CDCl3): d = 12.4 (CH i-Pr), 18.3 (CH3 i-Pr),
75.1 (CHOH), 103.2 (C-3), 122.2 (Cq), 126.6 (C-4), 126.5 (CHPh),
127.6 (CHPh), 128.6 (CHPh), 131.6 (Cq), 132.0 (C-2), 142.1 (C-6),
144.0 (Cq), 153.8 (Cq).
Tetrahedron 2007, 63, 1031.
(3) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell, N. A.;
Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 6226.
(4) Thibault, C.; L’Heureux, A.; Bhide, R. S.; Ruel, R. Org. Lett.
2003, 5, 5023.
(5) Minakata, S.; Komatsu, M.; Ohshiro, Y. Synthesis 1992,
661.
(6) During the referee process, an alternative syntheses of 6-
cyano-7-azaindole(4) was reported, see: Storz, T.;
Bartberger, M.; Sukit, S.; Wilde, C.; Soukup, T. Synthesis
2008, 201.
HRMS: m/z [M + H]+ calcd for C23H33N2O28Si: 381.2362; found:
381.2378.
(7) An Minakata, S.; Hamada, T.; Komatsu, M. J. Agric. Food
Phenyl(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-
yl)methanone (24)
Chem. 1997, 45, 2345.
(8) Benoît, S.; Gringas, S.; Soundara, N. PCT Int. Appl. WO
2003082289, 2003; Chem. Abstr. 2003, 139, 307795.
(9) Fife, W. K. J. Org. Chem. 1983, 48, 1375.
(10) Vorbrüggen, H.; Krolikiewicz, K. Synthesis 1983, 316.
(11) It is noteworthy that using Et3N stored on KOH, the reaction
did not work.
(12) (a) Guillaumet, G.; Savelon, L.; Viaud, M. C.; Pavli, P.;
Renard, P.; Pfeiffer, B.; Caignard, D. H.; Bizo-Espiard, J. G.
Eur. Pat. Appl. EP 691339, 1996; Chem. Abstr. 1996, 124,
261019p. (b) Mazéas, D.; Guillaumet, G.; Viaud, M. C.
Heterocycles 1999, 50, 1065.
To a stirred solution of alcohol 23 (0.410 g, 1.08 mmol) in toluene
(30 mL) under an argon atmosphere was added manganese dioxide
(0.939 g, 10.80 mmol). The reaction mixture was stirred under re-
flux with a Dean–Stark trap for 20 h. After filtration through celite,
the filtrate was evaporated under reduced pressure and the crude
product was purified by flash chromatography (PE–CH2Cl2, 5:5
then 0:10) to provide the protected ketone.
Yield: 68%; colourless oil.
IR (NaCl): 1651, 2948 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.13 (d, J = 7.5 Hz, 18 H, CH3 i-
Pr), 1.88 (sept, J = 7.5 Hz, 3 H, CH i-Pr), 6.65 (d, J = 3.5 Hz, 1 H,
H-3), 7.39 (d, J = 3.5 Hz, 1 H, H-2), 7.46–7.61 (m, 3 H, ArH), 7.84
(d, J = 7.9 Hz, 2 H, ArH), 8.36 (d, J = 2.2 Hz, 1 H, H-4), 8.78 (d,
J = 2.2 Hz, 1 H, H-6).
13C NMR (63 MHz, CDCl3): d = 12.3 (CH i-Pr), 18.1 (CH3 i-Pr),
104.4 (C-3), 121.5 (Cq), 126.1 (C-4), 128.3 (CHPh), 129.9 (CHPh),
130.6 (CHPh), 132.1 (C-2), 132.9 (Cq), 138.4 (Cq), 145.3 (C-6),
155.7 (Cq), 196.2 (Cq).
(13) Estel, L.; Marsais, F.; Quéguiner, G. J. Org. Chem. 1988, 53,
2740.
(14) (a) Leusink, A. J.; Budding, H. A.; Drenth, W.
J. Organomet. Chem. 1968, 11, 541. (b) Wollenberg, R. H.;
Albizati, K. F.; Peries, R. J. Am. Chem. Soc. 1977, 99, 7365.
(15) Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H.
Heterocycles 1992, 34, 2379.
(16) Moyer, M.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986,
51, 5106.
(17) Brière, J.-F.; Dupas, G.; Quéguiner, G.; Bourguignon, J.
Heterocycles 2000, 52, 1371.
HRMS: m/z [M + H]+ calcd for C23H31N2O28Si: 379.2206; found:
379.2219.
(18) N’Ait Ajjou, A.; Muzart, J.; Savelon, L.; Guillaumet, G.
Synthesis 1993, 539.
(19) L’Heureux, A.; Thibault, C.; Ruel, R. Tetrahedron Lett.
2004, 45, 2317.
Acknowledgment
(20) Bourguignon, G.; Quéguiner, G. J. Heterocycl. Chem. 1989,
26, 1029.
The Authors thank the ACI ‘Molécules et cibles thérapeutiques’
(CP) and Les Laboratoires Servier (CEB) for financial support.
(21) Bhupathy, M.; Conlon, D.; Wells, K.; Nelson, J.; Reider, P.;
Rossen, K.; Sager, J.; Volante, R.; Dorsey, B.; Hoffman, J.;
Joseph, S.; McDaniel, S. J. Heterocycl. Chem. 1995, 32,
1283.
References
(1) Mérour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471;
and references cited therein.
Synthesis 2008, No. 13, 2049–2054 © Thieme Stuttgart · New York