Synthesis of functionalized 7-azaindoles via directed ortho-metalations

Article abstract of DOI:10.1016/j.tetlet.2004.01.122

Functionalization at C-5 of 4-fluoro- and 4-chloro-1-triisopropylsilyl-7- azaindole, 1 and 2, respectively, leads to a variety of new substituted 7-azaindole derivatives. We also describe two approaches to introduce functionality at C-6.

Full text of DOI:10.1016/j.tetlet.2004.01.122

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 2317–2319
Synthesis of functionalized 7-azaindoles via directed
ortho-metalationsq
*
ꢀ
Alexandre LÕHeureux, Carl Thibault and Rejean Ruel
Bristol-Myers Squibb, Institut de recherche pharmaceutique, 100 boul. de l’Industrie, Quꢀebec, Candiac, Canada J5R 1J1
Received 26 November 2003; revised 19 January 2004; accepted 23 January 2004
Abstract—Functionalization at C-5 of 4-fluoro- and 4-chloro-1-triisopropylsilyl-7-azaindole, 1 and 2, respectively, leads to a variety
of new substituted 7-azaindole derivatives. We also describe two approaches to introduce functionality at C-6.
ꢀ 2004 Elsevier Ltd. All rights reserved.
7-Azaindole derivatives may be considered as useful
indole bioisosteres in medicinal chemistry and func-
tionalization at C-2 and C-3 of the 7-azaindole ring
system is well described in the scientific literature. Sub-
stitution of the pyrrole ring has been effected either
directly on the 7-azaindole core or, alternatively, by
cyclization of a requisite pyridine precursor.1 On the
other hand, the limited number of examplesof 4-, 5-,
and 6-substituted 7-azaindoles reported thus far have
been synthesized almost exclusively from functionalized
pyridine precursors.1 Consequently, we wish to describe
herein efficient proceduresfor the functionalization at
C-5 and C-6 of the 7-azaindole ring system. In addition,
an application of thismethodology yielding an
improved synthesis of 5-hydroxy-7-azaindole (6) is
described.
of N-fluorobenzenesulfonimide (NFSI),5 4,5-difluoro-7-
azaindole 3a wasobtained in 70% yield. Introduction
6
of chloride or bromide at C-5 wasbest carried out when
hexachloroethane or carbon tetrabromide wasuesd as
electrophiles. In the latter case, the use of N-bromo-
succinimide resulted in the isolation of bromide 3c in
only 26% yield (entry 4), along with 38% yield of the
product resulting from bromination at C-3. Interest-
ingly, thiscompetitive electrophilic proceswasminor
with 4-chloro-1-triisopropylsilanyl-7-azaindole (2) and
bromide 4c (entry 12) wasioslated in 68% yield with
7
NBS and 80% when CBr4 wasused asthe electrophile.
Control experiments without any added base showed
rapid formation of the 3-bromo regioisomers in both the
4-fluoro and 4-chloro series.
The preparation of 5-hydroxy-4-fluoro-7-azaindole 3f
and 5-hydroxy-4-chloro-7-azaindole 4f wasbtes
accomplished using camphorsulfonyloxaziridine8 and
Ti(i-PrO)4/t-BuOOLi.9 The former led to only 60%
conversion to the alcohol 3f and 58% isolated yield,
while the latter led to complete conversion to the alcohol
albeit in 50% isolated yield. In the case of 5-amino-7-
azaindoles 3e and 4e, the preparation wasaccomplished
using tosylazide10 asthe electrophile. The crude azide
formed wasthen directly reduced to the amine by cat-
alytic hydrogenation with palladium on charcoal in 30%
and 41% overall isolated yield, respectively (entries 6
and 14). Finally, the anion derived from N-triisoprop-
ylsilyl-4-chloro-7-azaindole (2) was treated with tri-
isopropylborate and the boronic acid was obtained in
47% yield after ester hydrolysis during the acidic work-
Table 1 summarizes the results we obtained when N-tri-
isopropylsilyl-4-fluoro-7-azaindole (1)2 and N-triiso-
propylsilyl-4-chloro-7-azaindole (2)3 were submitted to
directed ortho-metalation,4 followed by the addition of
an electrophile to the resulting anion to afford 4,5-
disubstituted-7-azaindoles 3 and 4, respectively (Scheme
1). The bulky silicon group prevents the lithiation at C-2
of the indole ring, therefore allowing metalation on the
pyridine ring. Consequently, when N-silylated-4-fluoro-
azaindole 1 wasallowed to react with 1.5 equiv of sec-
butyllithium at )78 ꢁC for 1 h, followed by the addition
Keywords: ortho-Metalation; 7-Azaindole.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.01.122
* Corresponding author. Tel.: +1-450-4446132; fax: +1-450-4444166;
e-mail: alexandre.lheureux@bms.com
11
up. Thisproduct wascoupled under Suzuki condition
to afford 4h (Scheme 1, E ¼ Ph) in 41% yield.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.122

2318
A. LÕHeureux et al. / Tetrahedron Letters 45(2004) 2317–2319
Table 1. Reactionsof metalated azaindole with electrophile
Entry
Reactant
Electrophile
Product R (3 or 4)
Yield (%)
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
NFSI
C2Cl6
F (3a)
Cl (3b)
70
68
63
26
87
30
58
50
60
86
80
68
79
66
65
60
47
2
3
CBr4
NBS
Br (3c)
Br (3c)
4
5
ClCO2Me
Tosylazide
CO2Me (3d)
NH2 (3e)
OH (3f)
OH (3f)
F (4a)
6
7
Camphorsulfonyloxaziridine
Ti(i-PrO)4/t-BuOOLi
NFSI
8
9
10
11
12
13
14
15
16
17
C2Cl6
CBr4
Cl (4b)
Br (4c)
Br (4c)
NBS
ClCO2Me
Tosylazide
CO2Me (4d)
NH2 (4e)
OH (4f)
OH (4f)
B(OH)2 (4g)
Camphorsulfonyloxaziridine
Ti(i-PrO)4/t-BuOOLi
B(O-i-Pr)3
TIPS
TIPS
N
TIPS
TIPS
N
N
N
N
X
N
X
N
N
a.
a.
HO
HO
E
Cl
Cl
4f
b.
2
1 X = F
2 X = Cl
3 X = F
4 X = Cl
TIPS
N
H
Scheme 1. Reagentsand conditions: (a) (i) sec-BuLi, 1.5 equiv, THF,
)78 ꢁC, 1 h; (ii) electrophile (E).
N
N
N
c.
HO
6
5
In summary, the above reaction conditions resulted in
clean ortho-metalationsat C-5 without any sign of halo-
gen scrambling,12 pyridyne formation,13 or competitive
lithiation at C-2.14
Scheme 2. Reagentsand condition:s (a) sec-BuLi, THF, )78 ꢁC,
camphorsulfonyloxaziridine; (b) Zn, AcOH, EtOH; (c) TBAF, THF.
The above methodology was also used to improve on
the previously reported syntheses of 5-hydroxy-7-aza-
indole (6). The synthesis of alcohol 6 wasfirst reported
by Robinson et al., starting from 7-azaindoline-N-oxi-
(LiTMP) in THF at )78 ꢁC and the resulting anion was
trapped with methylchloroformate to yield 6-carbo-
methoxy-4-chloro-5-fluoro-1-triisopropylsilyl-7-azaindole
(7) in 61% yield (Scheme 3).
de15 while the synthesis of the corresponding methyl
16
ether wasdecsribed by Viaud et al.
In the former
Alternatively, functionalization at C-6 could also be
carried out through a rearrangement involving an
appropriate N-oxide. Thisstrategy hasthe advantage of
providing access to 4,6-disubstituted azaindoles, as well
synthesis, a nonregioselective N-oxide rearrangement
with acetic anhydride wasreported to give a mixture of
5- and 6-acetoxyazaindoline, while the latter approach
involved an Ullman coupling of 5-bromo-7-azaindole.
We obtained alcohol 6 in three steps and 26% overall
yield starting from 4-chloro-1-triisopropylsilanyl-7-aza-
indole (2) (Scheme 2). Reduction of 4-chloro-5-hydroxy-
1-triisopropylsilanyl-7-azaindole (4f) with zinc in EtOH/
acetic acid gave 5-hydroxy-1-triisopropylsilanyl-7-aza-
indole (5) in 65% yield. The silicon group was then
removed using TBAF to provide 5-hydroxy-7-azaindole
(6) in 70% yield.
as4,5,6-triusbtsituted-7-azaindolesbearing non-
ortho-
directing functional groupsat the 5-poitsion. For
example, 4-chloro-7-azaindole-N-oxide 8 wasreacted
with methanesulfonyl chloride to give 4,6-dichloro-7-
azaindole (9) in 58% yield (Scheme 4). Thisproduct was
then protected with triisopropylsilyl chloride to give 4,6-
dichloro-1-triisopropylsilyl-7-azaindole (10) in 76%
yield. ortho-Metalation with sec-butyllithium, followed
Iterative lithiation leading to 4,5,6-trisubstituted 7-aza-
indolescan also be carried out when an ortho-directing
group isintroduced at C-5 although alkyllithium bases
could not be used due to aromatic nucleophilic substi-
tutionsof fluorine or chlorine at C-4. For example,
4-chloro-5-fluoro-1-triisopropylsilanyl-7-azaindole was
deprotonated with lithium tetramethylpiperidide
TIPS
N
TIPS
N
MeO2C
F
N
N
a.
F
4a
7
Cl
Cl
Scheme 3. Reagentsand conditions: LiTMP, THF, )78 ꢁC; ClCO2Me.

A. LÕHeureux et al. / Tetrahedron Letters 45(2004) 2317–2319
2319
4. Griffen, E. J.; Roe, D. G.; Snieckus, V. J. Org. Chem.
1995, 60, 1484–1485; Snieckus, V. Chem. Rev. 1990, 90,
879–933.
O
N
H
N
H
N
N
a.
5. (a) Differding, E.; Ofner, H. Synlett 1991, 187–189; (b)
Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy,
C. K.; Davis, F. A. Tetrahedron Lett. 1994, 3465–3468.
6. Typical procedure: A 10 mL oven-dried round-bottom
flask was evacuated and backfilled with argon. The flask
was charged with 4-fluoro-1-triisopropylsilanyl-1H-pyr-
rolo[2,3-b]pyridine (169 mg, 0.58 mmol), THF (4 mL) and
the mixture wascooled to )78 ꢁC. A sec-butyllithium
solution (263 lL, 1.10 M in cyclohexane, 2.2 equiv) was
added dropwise and after 30 min hexachloroethane
(342 mg, 1.45 mmol) in THF (4 mL) wasadded rapidly.
After 25 min, a solution of saturated ammonium chloride
wasadded and the mixture wasallowed to reach room
temperature and it wasextracted with ethyl acetate. The
combined organic layerswere wahsed with water, brine,
dried over Na2SO4, and concentrated in vacuo. The crude
material was purified using HPLC preparative reverse
phase (RP): Primesphereꢂ C-18-HC 21 · 100 mm column
with solvent system: solvent A: 10% acetonitrile/90%
water + 5 mM NH4OAc; solvent B: 90% acetonitrile/10%
water + 5 mM NH4OAc, with 20–100% B. Thisprocedure
2
8
Cl
Cl
b.
TIPS
N
H
Cl
N
Cl
N
N
c.
e.
10
d.
9
Cl
Cl
TIPS
TIPS
Cl
Cl
N
N
N
N
N3
H2N
11
12
Cl
Cl
Scheme 4. Reagentsand condition:s (a) m-CPBA, CHCl3; (b) Me-
SO2Cl, DMF, 80 ꢁC; (c) NaH, TIPSCl, THF, 80 ꢁC; (d) sec-BuLi,
THF, )78 ꢁC, tosylazide; (e) H2, Pd/C, EtOAc.
gave 136 mg (72%) of (3b) asa white oslid.
1H NMR
(400 MHz, CDCl3) d (ppm) 8.22 (1H, d, J ¼ 9:4 Hz), 7.30
(1H, d, J ¼ 3:6 Hz), 6.65 (1H, d, J ¼ 3:6 Hz), 1.86 (3H, m),
1.13 (18H, d, J ¼ 7:6 Hz). LCMS (solvent A: 10% aceto-
nitrile/90% water + 5 mM NH4OAc; solvent B: 90% ace-
tonitrile/10% water + 5 mM NH4OAc, with 50–100% B in
2 min gradient. Column Primesphere C4 4.6 · 30 mm, UV:
220 nm; Micromass ZMD 2000, ESI) m=z 327 (M + Hþ),
tR ¼ 2.11 min, purity ¼ 100%. HPLC (solvent A: 10%
acetonitrile/90% water + 0.05% TFA; solvent B: 90%
acetonitrile/10% water + 0.05% TFA, with 50–100% B in
2 min gradient. Column Primesphere C4 4.6 · 30 mm, UV:
220 nm) tR ¼ 2.28 min, purity ¼ 100%.
by addition of tosylazide to the resulting anion, gave 5-
azido-4,6-dichloro-1-triisopropylsilanyl-7-azaindole (11)
in 46% yield. Thisproduct can be reduced to 5-amino-
4,6-dichloro-1-triisopropylsilanyl-7-azaindole (12) using
catalytic hydrogenation in a quantitative yield.
In summary, we have demonstrated a new strategy for
the functionalization of 7-azaindoles leading to substi-
tution patterns difficult to obtain using existing meth-
odology. We have also described the application of this
new methodology in an improved synthesis of 5-
hydroxy-7-azaindole (6).
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Chem. 2001, 624, 47–52.
10. Spagnolo, P.; Zanirato, P.; Gronowitz, S. J. Org. Chem.
1982, 47, 3180–3183.
Acknowledgements
11. (a) Conditions: 4g, PhBr 1 equiv, PdCl2 dppf 0.1 equiv,
Cs2CO3 3 equiv, THF, 65 ꢁC, 3 h, yield 41% yield of 4h
(E ¼ Ph). (b) For an excellent review see: Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
We wish to thank Drs. Francis Beaulieu, Edward
ꢀ
Ruediger, Serge Benoit, and Stephane Gingrasfor
helpful discussions.
12. Mallet, M.; Branger, G.; Marsais, F.; Queguiner, G. J.
Organomet. Chem. 1990, 382, 319–332.
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^
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