Full functionalization of the 7-azaindole scaffold by selective metalation and sulfoxide/magnesium exchange

Article abstract of DOI:10.1002/anie.201303490

Filling positions: 7-Azaindoles are important targets in the pharmaceutical industry. All five carbon positions of the azaindole ring system can be functionalized in a predictable manner starting from the appropriately substituted azaindole 1 by directed metalation and halogen/magnesium and sulfoxide/magnesium exchange. The products are fully substituted azaindoles of type 2.

Full text of DOI:10.1002/anie.201303490

Angewandte
Chemie
DOI: 10.1002/anie.201303490
Synthetic Methods
Full Functionalization of the 7-Azaindole Scaffold by Selective
Metalation and Sulfoxide/Magnesium Exchange**
Nadja M. Barl, Elodie Sansiaume-Dagousset, Konstantin Karaghiosoff, and Paul Knochel*
Azaindoles are valuable targets in the pharmaceutical and
agrochemical industries due to their interesting cytotoxic
To this end, the sulfoxide group on C5 was found to be
essential for the full functionalization procedure, since it
allows both the direct metalation in ortho position and its
replacement by iodine using sulfoxide/magnesium
[
1]
activity. 7-Azaindole derivatives in particular have found
[
2]
[3]
applications as luminescent molecules and ligands. Thus,
synthetic methods for the simple construction and specific
functionalization of such N-heterocycles are indispensable. So
[
11,12]
exchange.
Hence, the key 7-azaindole 1 was prepared in
seven steps starting from the commercially available 2-amino-
[
4,5]
[6]
far, the Fischer
and Larock indole syntheses have been
5-bromopyridine (3). Thus, the regioselective iodination of 3
[13]
applied for preparing 7-azaindoles. Functionalization of this
heteroaromatic skeleton has also been successfully achieved
(HIO , I ) in a mixture of acetonitrile and acetic acid (808C,
4 2
5 h) produced the 3-iodopyridine 4 in 96% yield. Sonogashira
[7]
[14–16]
by Buchwald et al. Furthermore, the application of iterative
lithiation for the functionalization of 7-azaindoles has already
cross-coupling
of 4 with trimethylsilylacetylene in the
[17]
presence of 1 mol% [PdCl (PPh ) ] and 2 mol% CuI
2
3 2
[8]
been elegantly demonstrated by Snieckus et al. However,
a general and mild functionalization procedure allowing the
substitution of all the ring positions would be highly desirable.
Herein, we report the preparation of an appropriately
substituted 7-azaindole (1), which can undergo successive
functionalization of all five carbon positions of the azaindole
scaffold in a predictable manner. For achieving this synthetic
goal, we used a combination of directed magnesiations and
(258C, 1 h) led to aminopyridine 5 in 95% yield. Ring closure
of an intermediate sodium amide generated by addition of
[
18]
NaH in N-methylpyrrolidone (NMP) led, after one hour at
808C, to the desired 7-azaindole in 80% yield. Subsequently,
protection by a methoxymethyl (MOM) group (NaH, MOM-
Cl, DMF, 258C, 1 h) furnished the protected bromoazaindole
6 in 91% yield (73% yield over two steps). Selective lithiation
of 6 with TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) in
[
9]
[10]
[19]
lithiations as well as halogen/magnesium and sulfoxide/
THF (À608C, 1 h) and chlorination with PhSO Cl provided
2
[
11]
magnesium exchanges. To the best of our knowledge, this
procedure constitutes a novel methodology for the stepwise
full functionalization of these N-heterocycles, which allowed
us to prepare various polysubstituted 7-azaindoles of type 2
the dihalogenated 7-azaindole 7 in 82% yield. Thus, the newly
introduced chlorine substituent avoids a competitive metal-
ation in position 3 and serves as protecting group of the 2-
position. Br/Li exchange of 7 with nBuLi (À788C, 5 min) and
transmetalation with MgCl2 (0.5m in THF) followed by
sulfinylation using 4-methoxy-3,5-dimethylbenzenesulfinyl
(
Scheme 1).
[
11,12,20]
chloride
position 4
TMPMgCl·LiCl (À308C, 10 min) and quantitatively bro-
minated with (BrCl C) affording the key azaindole 1 in
gave azaindole 8 in 90% yield. Finally,
was regioselectively magnesiated using
[
21]
[22]
2
2
4
8% overall yield starting from 3 (Scheme 2).
The polyfunctional 7-azaindole scaffold 1 offers hidden
organometallic pathways for the functionalization of all five
carbon positions of the 7-azaindole scaffold. First the
functionalization of position 6 was achieved by using the
Scheme 1. The 7-azaindole scaffold 1 crucial for the preparation of fully
substituted 7-azaindoles of type 2. Ar=4-methoxy-3,5-dimethylphenyl.
[21]
highly chemoselective base TMPMgCl·LiCl
(1.50 equiv,
À108C, 10 min) leading to the magnesiated 7-azaindole 9.
Transmetalation of 9 with ZnCl (1m in THF, 1.50 equiv)
2
[23]
followed by a copper-mediated acylation (CuCN·2LiCl, 1m
[*] M. Sc. N. M. Barl, Dr. E. Sansiaume-Dagousset,
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
in THF, 1.50 equiv) with furan-2-carbonyl chloride
[22]
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, 81377 Mꢁnchen (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
(1.50 equiv) led to the 6-substituted azaindole 10 in 63%
[
22]
yield. Furthermore, iodolysis of 9 provided the iodide 11 in
1% yield, which proved to be an excellent intermediate for
further functionalization reactions. Thus, Sonogashira cross-
6
[
**] We thank the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007-2013;
ERC grant agreement no. 227763) and Novartis (Basel) for financial
support. We also thank BASF AG (Ludwigshafen), W. C. Heraeus
[14–16]
coupling
of 11 using 3 mol% [PdCl (PPh ) ], 6 mol%
2 3 2
CuI, Et N (10.0 equiv, 258C, 1 h) and 1.20 equiv of 1-octyne
3
furnished the expected alkyne 12 in 92% yield. Interestingly,
the lithiation of 1 with TMPLi (1.30 equiv, À788C) gave
a transient lithium reagent A which underwent a “halogen
(
Hanau), and Chemetall GmbH (Frankfurt) for generous gifts of
chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303490.
[
24]
dance” leading to the 4-lithiated 7-azaindole 13. The best
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10093

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Angewandte
Communications
[
10]
reagent using iPrMgCl·LiCl
(1.05 equiv, À408C). This
highly functionalized heterocyclic Grignard reagent was
trapped with various electrophiles (NC-CO Et, Cl-SiMe ,
Tos-CN, and ethyl (2-bromomethyl)acrylate ) leading to the
2
3
[
28]
[29]
expected 5-substituted azaindoles 16a–d in 68–97% yield.
7
-Azaindole 16a was then further functionalized in position 6
[30,31]
by performing Negishi cross-couplings
with para-substi-
tuted arylzinc reagents (1.30 equiv, 17a: R = CO Et; 17b:
2
R = CN) in the presence of 3 mol% [Pd(PPh ) ] (258C, 5–
3
4
1
2 h) to furnish the 6-arylated azaindoles 18a,b in 98 and 65%
yield, respectively (Scheme 4).
Scheme 2. Key steps in the synthesis of 7-azaindole 1 starting from
commercially available 2-amino-5-bromopyridine 3: a) HIO4
(
0.3 equiv), I (0.5 equiv), MeCN/AcOH, 808C, 5 h; b) trimethylsilylace-
2
tylene (1.2 equiv), [PdCl (PPh ) ] (1 mol%), CuI (2 mol%), Et N, 258C,
2
3
2
3
1
h; c) NaH (1.2 equiv), NMP, 808C, 1 h, 80%; d) NaH (1.2 equiv),
MOMCl (1.2 equiv), DMF, 258C, 1 h, 91%; e) TMPLi (1.1 equiv), À60
to À458C, 1 h, PhSO Cl (1.2 equiv), THF, 2 h; f) nBuLi (1.0 equiv),
2
À788C, 5 min, MgCl (0.5m in THF, 1.1 equiv), 4-methoxy-3,5-dime-
2
thylbenzenesulfinyl chloride (1.2 equiv), À78 to À308C; THF, 1 h;
g) TMPMgCl·LiCl (1.5 equiv), À308C, 10 min 1,2-dibromo-1,1,2,2-tetra-
chloroethane (1.2 equiv), À30 to 258C, THF, 2 h. Ar=4-methoxy-3,5-
dimethylphenyl.
yields were obtained by generating the lithiated intermediate
1
3 in the presence of the electrophile (Barbier in situ
[
25,26]
conditions
). Thus, in the presence of 1,1,2-trichloro-
Scheme 4. Functionalization of positions 5 and 6. X=Cl·LiCl.
1
,2,2-trifluoroethane (Cl FCCF Cl, 1.50 equiv), the corre-
2 2
[
22]
sponding 4-chloro-7-azaindole 14a was obtained in 91%
yield. Similarly, performing this lithiation in the presence of
The remaining position 3 of 18a was functionalized by
selective iodination with N-iodosuccinimide (2.20 equiv) in
CH Cl to give a 3-iodoazaindole in 87% yield. Subsequent I/
[22]
an excess of Me SiCl provided the silylated azaindole 14b
3
in 79% yield (Scheme 3).
2
2
[
10]
Mg exchange with iPrMgCl·LiCl (1.10 equiv) provided the
magnesium reagent 19, which was transmetalated using ZnCl
2
[
23]
(1.20 equiv) followed by a copper-mediated acylation with
furan-2-carbonyl chloride (2.00 equiv) to afford 20 in 68%
yield. Cyanation of 19 with TosCN (1.50 equiv) led to the
desired product 21 in 84% yield (Scheme 5).
[
32]
Selective dechlorination of 21
Schlosser method
according to the
[33]
with 3.00 equiv of HCO NH in the
2
4
Scheme 3. Functionalization of positions 6 and 4. X=Cl·LiCl; Ar=
4
-methoxy-3,5-dimethylphenyl.
The next functionalization was performed in position 5 by
[
11,12]
means of a sulfoxide/magnesium exchange.
Thus, treat-
[
10]
ment of 14a with iPrMgCl·LiCl (1.00 equiv) at À908C for
min led to a magnesium intermediate which was imme-
diately transmetalated with ZnCl2 (1.00 equiv) and then
treated with I . The resulting iodide 15 was obtained in
[
27]
2
2
Scheme 5. Functionalization of positions 3 and 2. X=Cl·LiCl; Ar’=
p-EtO CC H .
6
0% yield and conveniently converted to a magnesium
2
6
4
1
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Angewandte
Chemie
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