Preparation of azaindolines and benzoyl substituted azaindolines: Precursors of triazabenzo[cd]azulen-9-one PDE4 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2011.08.009

The syntheses of various substituted azaindolines are described. Azaindolines were identified as potential key intermediates towards new PDE4 inhibitors.

Full text of DOI:10.1016/j.tetlet.2011.08.009

Tetrahedron Letters 52 (2011) 5292–5296
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Tetrahedron Letters
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Preparation of azaindolines and benzoyl substituted azaindolines: precursors
of triazabenzo[cd]azulen-9-one PDE4 inhibitors
Matthew Badland b, , Ingrid Devillers a, , Corinne Durand a, Véronique Fasquelle a, Bernard Gaudillière a,
Henry Jacobelli a, Ajith C. Manage b, Isabelle Pevet a, Jocelyne Puaud a, Anthony J. Shorter b,
Roger Wrigglesworth a
⇑
⇑
a Pfizer Global Research and Development, Fresnes Laboratories, 3-9 Rue de la Loge, F-94265 Fresnes Cedex, France
b Evotec OAI Abingdon, 151 Milton Park, Abingdon, Oxon OX14 4SD, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of various substituted azaindolines are described. Azaindolines were identified as potential
key intermediates towards new PDE4 inhibitors.
Received 26 April 2011
Revised 22 June 2011
Accepted 1 August 2011
Available online 16 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azaindolines
PDE4
Inhibitors
Pyridine
Phosphodiesterases (PDEs) are important enzymes, participat-
ing in cellular regulation of the secondary messengers, cAMP or
cGMP, and are often targets for pharmacological inhibition due to
their unique tissue distribution, and structural and functional
properties. Inhibitors of PDEs can prolong or enhance the effects
of physiological processes mediated by cAMP or cGMP by inhibi-
tion of their degradation. Following the classification proposed
by Beavo,1 the different PDE isoforms can be grouped into eleven
major families (PDE1–11). PDE4 is a specific cAMP isoenzyme, that
is, particularly abundant in airway smooth muscle, immune and
inflammatory cells, and is therefore considered as a potential
molecular target for the development of new immunomodulatory
and anti-inflammatory drugs.
As part of a research programme aimed to develop novel, selective
PDE4 inhibitors we investigated the synthesis of nitrogen isosteres 2
of the previously reported2,3 promising benzodiazepine skeleton 1.
The retrosynthetic analysis we envisaged is shown in Scheme 1
with key steps in the synthesis being the preparation of 7-substi-
tuted 4- and 6-azaindoline derivatives 3 and 4. To the best of our
knowledge, there are only a few citations for the preparation of
6-azaindolines 5 reported in the literature,4–6 and fewer still con-
cerning the 4-azaindoline 6. Most of the methodologies described
concerned 5-azaindoline chemistry.7 We therefore focussed our
attention on the development of a convergent and practical
synthesis of these new azaindoline building blocks and our results
are reported herein.
Our initial attempts focussed on preparing the appropriate
starting 2,4-disubstituted-3-aminopyridine 7. Again, this class of
compound is not well documented in the literature with the few
examples cited concerning the synthesis of the antiviral and
antitumor agents, nevirapine8 and streptonigrin.9
The synthesis started with the conversion of 2-methoxy-5-ami-
nopyridine into the corresponding carbamate, 8 which allowed the
introduction of electrophiles at the C4 position via ortho-lithiation
chemistry.10,11 ortho-Directed lithiation of tert-butyl pyridin-3-ylc-
arbamates 8 occurred to furnish 4-substituted derivatives 9 in
acceptable yields (Table 1). In the case where the electrophile
was 2-bromoethanol, the resulting amino alcohol 9 was cyclised
directly into 6-azaindoline 11 (Scheme 2).
This strategy initially appeared promising as we could hopefully
introduce the desired functionality to provide both regioisomers
and obtain access to 2,4-disubstituted-3-aminopyridines. How-
ever, all attempts to metallate the original C2-position of either 9
or 11 and introduce the second desired group, E2 failed.
With the directed metallation chemistry not providing access to
2,4-disubstituted-3-aminopyridines 7, we next investigated the
introduction of the desired functional group at the C2-position
first. This was achieved in good yield by
a metal–halogen
exchange reaction (Table 2), but again directed metallation at the
C4-position using a variety of reagents such as LDA, LiTMP or t-BuLi
was not successful (Scheme 3).
⇑
Corresponding authors. Tel.: +44 0 1304 642399 (M.B.).
E-mail address: matthew.badland@pfizer.com (M. Badland).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.009

M. Badland et al. / Tetrahedron Letters 52 (2011) 5292–5296
5293
O
N
NR
O
NR
E1
H
N
N
R
X
R
N
R
N
O
N
6-azaindoline
E1
1, X=C
3
5
2a, X=N
NH2
E2
R
N
7
O
N
NR
NR
N
N
H
N
N
N
O
R
O
E1
R
R
N
4-azaindoline
2b
4
6
Scheme 1. Retrosynthetic analysis of triazabenzo[cd]azulen-9-one.
Table 2
Table 1
ortho-Directed metallation results
Metal–halogen exchange reaction results
E1
Yield % of 9
Entry
R
E2
Yield % of 14
Entry
R
1
2
3
H
H
H
PhCONMe2
PhCONMe2
PhCOH
71
71
64
OH
OH
1
2
H
7
Br
MeO
58
Br
O
OH
OH
4
5
MeO
MeO
58
58
Br
Br
3
4
MeO
MeO
67
68
PhCONMe2
Although we failed to access the 2,4-disubstituted-3-amino-
pyridines we were able to produce 6-azaindoline 11 and antici-
pated that we could also access 4-azaindolines by a similar route.
This was demonstrated (Scheme 4) using the methoxy-substituted
aminopyridine 15 as more electron-rich methoxy-substituted pyr-
idine rings gave increased yields and offered the potential for fur-
ther functionalisation. The amino alcohols 16 and 20 could be
cyclised in one step, but a two-step process via the mesylate and
LiHMDS treatment was preferred as this led to better overall yields
of azaindolines 18 and 21 .6
As previously demonstrated, directed metallation of Boc-pro-
tected 3-aminopyridine provided a poor yield of tert-butyl [4-(2-
hydroxyethyl)pyridin-3-yl]carbamate 9 (Table 1, entry 1). As a re-
sult, alternative chemistry to obtain unsubstituted azaindolines
was sought. An alternative synthesis of 9 via nucleophilic aromatic
substitution followed by routine functional group transformations
was investigated (Schemes 5 and 6) as a way of accessing both 4-
and 6-azaindolines.
2-Chloro-3-nitropyridine (22) was reacted with diethyl malon-
ate or ethyl acetoacetate in accordance with the literature.12 Krap-
E1
E1
NHBoc
NHBoc
H
NHBoc
E2
R
N
H
Route 2
R
N
R
N
8
9
10
OH
Route 1
E1 =
Br
NHBoc
E2
NHBoc
H
R
N
R
N
11
12
Scheme 2. Directed metallation of Boc-protected 3-aminopyridines.

5294
M. Badland et al. / Tetrahedron Letters 52 (2011) 5292–5296
E1
NHBoc
NHBoc
Br
Conditions, E1
n-BuLi, THF, E 2
NHBoc
E2
R
N
R
N
E2
R
N
14
10
13
Scheme 3. Initial route to 4-disubstituted-3-aminopyridines.
OH
OMs
OtBu
H
H
N
N
c
N
O
O
d
O
O
O
MeO
N
MeO
N
MeO
N
a, b
18
16
17
NH2
MeO
N
15
O
OtBu
NHBoc
Br
NHBoc
OH
N
b'
e, f
c', d'
MeO
N
MeO
N
MeO
N
19
20
21
Scheme 4. Synthetic route for the preparation of 5-methoxy 4- and 6-azaindolines. Reagents and conditions: (a) Boc2O, 1,4-dioxane, 96%; (b) n-BuLi, TMEDA, ethylene oxide,
Et2O, ꢀ78 °C, 57%; (c) Et3N, MsCl, CH2Cl2, 90%; (d) LiHMDS, THF, ꢀ78 °C, 91%; (e) HBr, H2O2, 97%; (f) Boc2O, NaHMDS, THF, 78%; (b0) 58%; (c0) 94%; (d0) 63%.
NO2
Cl
NO2
CO2Et
NO2
CO2Et
NH2
CO2Et
b
c
a
N
N
N
N
22
23
24
25
O
O
OtBu
NH2
NHBoc
N
d
e
f, g
N
OH
N
OH
N
26
27
28
Scheme 5. Synthetic route to unsubstituted 4-azaindoline 28. Reagents and conditions: (a) CH3COCH2CO2Et, NaH, THF, 84%; (b) HCl, EtOH, quant.; (c) H2, Pd/C wet, EtOH,
92%; (d) LiBH4, THF, 39%; (e) Boc2O, 1,4-dioxane, 41%; (f) MsCl, CH2Cl2, 99%; (g), LiHMDS, THF, ꢀ78 °C, 98%.
O
O
O
OH
Cl
EtO
EtO
NO2
NO2
NO2
a, b
c
d
N
N
N
N
29
30
31
32
EtO2C
HO
H
H
N
NH
N
O
O
e, f
h
g
N
N
N
33
34
35
Scheme 6. Synthetic route to unsubstituted 6-azaindoline 35. Reagents and conditions: (a) HNO3, H2SO4, 76%; (b) POCl3, toluene, 67%; (c) CH3COCH2CO2Et, NaH, DMF, 100%;
(d) HCl, EtOH, 41% (over 2 steps); (e) H2, Pd/C wet, EtOH, 91%; (f) t-BuCOCl, Et3N, CH2Cl2, 89%; (g) DIBAL, THF, 38%; (h) HCl (12 M), 26%.

M. Badland et al. / Tetrahedron Letters 52 (2011) 5292–5296
5295
OtBu
NH
Br
N
NH
HCl (2 M, Et2O)
Bu4NBr3
O
CHCl3
50%
87%
MeO
N
MeO
N
MeO
N
36
18
37
HBr, H2O2
75%
Scheme 7. Bromination conditions.
Table 3
Summary of reaction conditions
Entry
Reactant
Conditions
Product
Yield (%)
40
O
N
1
38a
n-BuLi, TMEDA, ꢀ78 °C, PhCONMe2
MeO
N
N
O
N
2
38b
n-BuLi, TMEDA, ꢀ78 °C, PhCONMe2
Not determined
MeO
39a
39b
39c
39c
39c
3
4
5
6
7
38a
38b
37
37
37
CuCN, DMF,
CuCN, DMF,
CuCN, DMF,
CuCN, DMF, (MW)
Zn(CN)2, Pd2(dba)3, dppf
D
D
D
33
34
Not determined
54
74
b
NH
NR
NR
NH
Br
d
a
c
O
MeO
N
MeO
N
Br
MeO
N
CN
MeO
N
37
38
39
40
R= pivaloyl 38a
R= acetyl 38b
R= pivaloyl 39a
R= acetyl 39b
R= H 39c
Scheme 8. Functional group transformation of 6-azaindoline 37. Reagents and conditions: (a) t-BuCOCl or CH3COCl, Et3N, CH2Cl2, 70%; (b) n-BuLi, TMEDA, ꢀ78 °C,
PhCONMe2; (c) Zn(CN)2, Pd2(dba)3, dppf, DMF, 130 °C, 74%; (d) PhMgBr, THF, 0 °C, 58%.
cho-type decarboxylation of the diethyl malonate derivative was
found to be less efficient than deacylation of ethyl 2-(3-nitropyri-
din-2-yl)-3-oxobutanoate (23). Deacylation was achieved in quan-
titative yield using ethanolic hydrogen chloride leading to ethyl 2-
(3-nitropyridin-2-yl)acetate (24).13 Sequential reduction of the ni-
tro14 and carboxylate functions provided the amino alcohol 26 con-
taminated with the corresponding azaindoline product. Boc-
protected amino alcohol 27 was then cyclised as previously dem-
onstrated. These route developments led to the preparation of
the unsubstituted 4-azaindoline building block 28 (Scheme 5).
Similar chemistry starting from 4-chloro-3-nitropyridine (30)
led to the unsubstituted 6-azaindoline building block 35 (Scheme
6).
conditions15,16 that provided the required bromo compound 37
in good yield, as shown in Scheme 7.
Attempts to introduce the benzoyl group by metal–halogen ex-
change of the bromine atom were performed without any success,
returning only the des-bromo analogues, which provides evidence
for metal–halogen exchange but an inability to react with the de-
sired electrophiles (Table 3, entries 1 and 2).
Cyanation of azaindoline 37 or the N-protected compounds 38a
and 38b (Scheme 8) showed promising results (Table 3). The use of
microwave chemistry under Rosenmund–von Braun conditions
(entry 6) gave an improved yield compared to traditional heating
conditions (entries 3–5) and the option to start without a protect-
ing group in place.
Having four new azaindoline building blocks 18, 21, 28 and 35
in hand we next turned our attention to installing the benzoyl
group at position 7 of the azaindolines.
Attempted bromination using elemental bromine failed to give
the desired product, but we quickly identified successful
Palladium-catalysed reaction conditions led to the desired com-
pound 39c in a high 74% yield (entry 7). Conversion of the resulting
nitrile 39c into the required benzoyl substituted azaindoline 40
was achieved by addition of phenylmagnesium bromide followed
by imine hydrolysis during work-up (Scheme 8).

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M. Badland et al. / Tetrahedron Letters 52 (2011) 5292–5296
OH
NBoc
OH
NH2
NHBoc
OMe
NBoc
OMe
e
a, b
c, d
N
OMe
N
N
N
41
42
43
44
NH
Cl
NH
CN
NH
f
g
h
O
N
N
N
46
45
47
Scheme 9. Preparation of 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-7-yl(phenyl)methanone 47. Reagents and conditions: (a) Boc2O, 1,4-dioxane, quant.; (b) n-BuLi, TMEDA,
ethylene oxide, Et2O, ꢀ78 °C, 57%; (c) MsCl, CH2Cl2, 99%; (d), LiHMDS, THF, ꢀ78 °C, 85%; (e) NaSCH3, DMF, 100 °C, 16 h, 57%; (f) POCl3, toluene, 90 °C, 7 h, 30%; (g) Zn(CN)2,
Pd2(dba)3, dppf, DMF, 130 °C, 41%; (h) PhMgBr, THF, 0 °C, 58%.
3. Burnouf, C.; Auclair, E.; Avenel, N.; Bertin, B.; Bigot, C.; Calvet, A.; Chan, K.;
An alternative approach using the methoxy group required the
preparation of 7-methoxy-6-azaindoline 43 and this was carried
Durand, C.; Fasquelle, V.; Féru, F.; Gilbertsen, R.; Jacobelli, H.; Kebsi, A.; Lallier,
E.; Maignel, J.; Martin, B.; Milano, S.; Ouagued, M.; Pascal, Y.; Pruniaux, M.-P.;
out using previously described conditions, as shown in Scheme 9.
Successful demethylation of 7-methoxy-6-azaindoline 43 led to
the pyridone 44. The chloropyridine derivative 45 was prepared
using standard conditions which gave access to the targeted ben-
zoyl azaindoline derivative 47, again following previously identi-
fied cyanation and phenyl Grignard addition procedures.
In conclusion, we have demonstrated that useful substituted
azaindoline synthons 18, 21, 28, 35 and 43 can be generated
through the use of the chemistry described herein. These mole-
cules are flexible building blocks that can be easily functionalised
to give products such as 40 and 47. This chemistry can be applied
to the synthesis of nitrogen isosteres of tetrahydrodiazepinoin-
doles1,2 expanding on work previously reported.17
Puaud, J.; Rocher, M.-N.; Terrasse, C.; Wrigglesworth, R.; Doherty, A. M. J. Med.
Chem. 2000, 43, 4850.
4. De Bie, D. A.; Ostrowicz, A.; Geurtsen, G.; Van der Plas, H. C. Tetrahedron 1988,
44, 2977.
5. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687.
6. Peglion, J.-L.; Vilaine, J.-P.; Villeneuve, N.; Thollon, C.; Bourguignon, M.-P.;
Poitevin, C., EP 1197485 A1, 2002; Chem. Abstr. 2002, 136, 309939.
7. Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64, 9430.
8. Kelly, T. A.; Proudfoot, J. R.; McNeil, D. W.; Patel, U. R.; David, E.; Hargrave, K. D.;
Grob, P. M.; Cardozo, M.; Agarwal, A.; Adams, J. J. Med. Chem. 1995, 38, 4839.
9. Godard, A.; Rovera, J. C.; Marsais, F.; Ple, N.; Quéguiner, G. Tetrahedron 1992, 48,
4123.
10. Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059.
11. Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med.
Chem. 1988, 31, 2136.
12. Liu, M. C.; Lin, T. S.; Sartorelli, A. C. Synth. Commun. 1990, 20, 2965.
13. Atwell, G. J.; Sykes, B. M.; O’Connor, C. J.; Denny, W. A. J. Med. Chem. 1994, 37,
371.
14. Robinson, R. P.; Donahue, K. M.; Son, P. S.; Wagy, S. D. J. Heterocycl. Chem. 1996,
33, 287.
Supplementary data
15. Berthelot, J.; Guette, C.; Desbene, P. L.; Basselier, J. J.; Chaquin, P.; Masure, D.
Can. J. Chem. 1989, 67, 2061.
16. Dunn, A. D.; Currie, A.; Hayes, L. E. J. Prakt. Chem. 1989, 331, 369.
17. Devillers, I.; Pevet, I.; Jacobelli, H.; Durand, C.; Fasquelle, V.; Puaud, J.;
Gaudillière, B.; Idrissi, M.; Moreau, F.; Wrigglesworth, R. Bioorg. Med. Chem.
Lett. 2004, 14, 3303.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.009.
References and notes
1. Beavo, J. A. Physiol. Rev. 1995, 75, 725.
2. Pascal, Y.; Andrianjara, C. R.; Auclair, E.; Avenel, N.; Bertin, B.; Calvet, A.; Feru,
F.; Lardon, S.; Moodley, I.; Ouagued, M.; Payne, A.; Pruniaux, M.-P.; Szilagyi, C.
Bioorg. Med. Chem. Lett. 2000, 10, 35.