General methods for the synthesis and late-stage diversification of 2,4-substituted 7-azaindoles

Article abstract of DOI:10.1016/j.tetlet.2016.09.029

As part of a medicinal chemistry program, we adapted known synthetic methods for the late-stage diversification of 2,4-substituted 7-azaindoles. The strengths and weaknesses of these strategies are discussed. In the course of this work, three optimized co

Full text of DOI:10.1016/j.tetlet.2016.09.029

Accepted Manuscript
General methods for the synthesis and late-stage diversification of 2,4-substi-
tuted 7-azaindoles
Jeffrey G. Varnes, Thomas McGuire, Rebecca E. Meadows, Bernard Barlaam,
Jemma Clark, Calum R. Cook, Gemma Davison, Allan Dishington, Chris De
Savi, Craig Donald, Tyler Grebe, Sudhir Hande, Janet Hawkins, Alexander W.
Hird, Jane Holmes, Andrew Lister, Simon Lucas, Jane Moore, Esther Moore,
Anil Patel, Kurt G. Pike, Bryan Roberts, Andrew Stark, Darren Stead, Kumar
Thakur, Paul Turner, Melissa Vasbinder, Bin Yang
PII:
S0040-4039(16)31189-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.029
TETL 48099
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 July 2016
2 September 2016
7 September 2016
Please cite this article as: Varnes, J.G., McGuire, T., Meadows, R.E., Barlaam, B., Clark, J., Cook, C.R., Davison,
G., Dishington, A., Savi, C.D., Donald, C., Grebe, T., Hande, S., Hawkins, J., Hird, A.W., Holmes, J., Lister, A.,
Lucas, S., Moore, J., Moore, E., Patel, A., Pike, K.G., Roberts, B., Stark, A., Stead, D., Thakur, K., Turner, P.,
Vasbinder, M., Yang, B., General methods for the synthesis and late-stage diversification of 2,4-substituted 7-
azaindoles, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.09.029
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General methods for the synthesis and late-stage diversification of 2,4-
substituted 7-azaindoles.
a,
Jeffrey G. Varnes ∗, Thomas McGuire , Rebecca E. Meadows , Bernard Barlaam , Jemma
b
c
b
b
b
b
b
Clark , Calum R. Cook , Gemma Davison , Allan Dishington , Chris De Savi , Craig
a
b
Donald , Tyler Grebe , Sudhir Hande , Janet Hawkins , Alexander W. Hird , Jane Holmes ,
a
a
b
a
b
b
b
b
b
b
b
Andrew Lister , Simon Lucas , Jane Moore , Esther Moore , Anil Patel , Kurt G. Pike ,
b
Bryan Roberts , Andrew Stark , Darren Stead , Kumar Thakur , Paul Turner , Melissa
c
b
a
b
a
a
Vasbinder , Bin Yang .
a
Oncology Chemistry, Innovative Medicines Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
b
Oncology Chemistry, Innovative Medicines Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
c
Chemical Development, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
As part of a medicinal chemistry program, we adapted known synthetic methods for
the late-stage diversification of 2,4-substituted 7-azaindoles. The strengths and
weaknesses of these strategies are discussed. In the course of this work, three
optimized conditions were identified from an iterative catalyst screen for the
conversion of Boc-protected 4-chloro-2-(piperidin-4-yl)-7-azaindole to the
corresponding pinacol borate ester. Additionally, a scalable route to previously
unreported Boc-protected 4-bromo-2-(piperidin-4-yl)-7-azaindole and efficient
conversion to the corresponding pinacol borate ester in 72% isolated yield are also
disclosed.
Received in revised form
Accepted
Available online
Keywords:
7
-azaindole
Miyaura borylation
Suzuki-Miyaura reaction
2
016 Elsevier Ltd. All rights reserved
1
2
H-pyrrolo[2,3-b]pyridine
-(piperidin-4-yl)-7-azaindole
Azaindoles have generated significant interest as both synthetic targets and key structural components of
1
1d
therapeutic agents. As indole or purine isosteres , these moieties offer opportunities to modulate physical properties
through nitrogen incorporation at the 4-, 5-, 6-, or 7- position, and the variety of potential substitution patterns
1a-c
provides significant opportunity for chemical route development . Of particular therapeutic interest is the use of 7-
azaindoles as kinase inhibitors, where the nitrogens of the pyridine and pyrrole rings can act as a hydrogen bond
acceptor and donor pair, respectively, in forming interactions with the protein backbone of the ATP binding site
1
d
(
Figure 1A).
4
2
1
7
H
N
A
1
2
Figure 1. (A) Simplified hydrogen bond interactions between a 2- (R
1
) and 4- (R
2
) substituted 7-azaindole and the protein backbone of a
kinase in the ATP binding site. 1 & 2 are literature examples of 7-azaindole CDK9 and BTK inhibitors, respectively.
As part of a medicinal chemistry effort, we became interested in the preparation of 2,4-substituted 7-azaindoles
such as 1 and 2 (Figure 1), which have been reported in the literature as inhibitors of cyclin-dependent kinase 9
2
a-d
2e-f
CDK9) and Bruton’s tyrosine kinase (BTK) , respectively. We were keen to develop and optimize cost-effective,
(
broadly applicable, and scalable methods for rapid late-stage elaboration of C2 and C4 substituents in order to support
internal compound demand for structure-activity relationship (SAR) exploration and in vivo testing. Herein we use
compound 1 and related analogs to describe these efforts.
∗
Corresponding author. Tel.: +1-781-839-4944; fax: +1-781-839-4630; e-mail: jeffrey.varnes@astrazeneca.com

3
Our initial route to prepare 1 and related analogs is described in Scheme 1. Starting from bromide 3, which was
either purchased from a commercial supplier or prepared from 4-bromo-7-azaindole and tosyl chloride (NaH, DMF;
yield: 96%) , lithiation with LDA (generated in situ) followed by an iodine quench afforded 4 in excellent yield.
4
5
2
a
Suzuki-Miyaura coupling conditions using Pd(PPh ) preferentially afforded desired carbamate 5 , while higher
3 4
n
d
6
temperatures, long reaction times, or more reactive catalysts (e.g., XPhos 2 Generation Precatalyst ) generally
eroded C2 selectivity and drove concomittant oxidative addition at C4. A second Suzuki coupling with 4-fluoro-2-
methoxyphenyl boronic acid and XPhos 2 Generation Precatalyst smoothly provided 6, and the tosyl protecting
nd
group was then removed under basic conditions. Yields for deprotection were variable, however, improved yields
could generally be obtained using either a) anhydrous conditions and powdered sodium hydroxide or b) aqueous
NaOH or KOH with careful reaction monitoring so as to avoid protracted reaction times.
a
b
c
3
4
5
6
Ar =
d
c
a
e
1
0
8
7
9
1
1
1a, ketone = 1-benzylpyrrolidin-3-one
1b, ketone = 1-Boc-pyrrolidin-3-one
f
Scheme 1. a) nBuLi, DIA, I
2
, 2-Me-THF, -78 °C, 4: 93%; 10: 75%; b) RBPin, Pd(PPh
XPhos 2 Generation Precatalyst, K PO , dioxane/H
9%; e) 10 wt% Pd/C, MeOH, 55 °C, 98%. f) 11a: ketone, LDA, THF, -78 °C, 28%; 11b: ketone, LaCl
3
)
4
, K
2
CO
3
, dioxane/H
2
2
O, 85 °C, 79%; c) ArB(OH) ,
nd
3
4
2
O, 6: 100 °C, 87%; 9: 80 °C, 90%; d) KOH or NaOH, dioxane/H
2
O, 60 to 80 °C, 50-
.
8
3
2 LiCl, LDA, THF, -78 °C, 32%.
Hydrogenation of 7 was accomplished at elevated temperature to provide piperidine 8, and the Boc protecting
group could be removed under standard conditions (TFA/DCM or 4N HCl in dioxane) to afford 1. Good yields for
conversion of 7 to 8 required a hot methanol wash of the catalyst to ensure full recovery, and these conditions are
2a,c
similar to those previously disclosed.
hydrogenated successfully at room temperature.
More elaborate scaffolds containing similar olefins, however, have been
7
Where a specific C4 substituent was desired (e.g., Ar = 4-F-2-OMe-Ph), the preparation of intermediates such as
0 promoted rapid late-stage C2 diversification under Pd-mediated conditions. We also investigated deprotonation of
1
9
2a,c,e-f,3,8
and addition to electrophiles other than iodine. Such work has been previously reported
for similar
substituted and unsubstituted 7-azaindoles, but only one example existed at the time of this writing where a phenyl
2a,c
group was exemplified at C4. Yields were typically modest (~<30%) for successful additions when using lithium
diisopropylamide (LDA) as base, and this was attributed to competing ketone alpha-deprotonation, as evidenced by
3
significant amounts of recovered starting material. For 11b, salts such as LaCl facilitated addition, and this has been
8
a
3
exemplified previously using CeCl .
Generally we were satisfied with the route depicted in Scheme 1, as it allowed customization of C2 and C4
substituents. However, this route suffered from being lengthy (6 steps with deprotection) and did not accommodate C4
exploration as the final step. Additionally, we were unable to readily incorporate hydrogenation-labile functionalities.
Groups susceptible to strong base were also disadvantaged, and, as a result, we sought a more concise synthesis that
offered multiple points of diversification while also being more functionally tolerant.
For design hypotheses revolving around specific C2-substituents such as piperidin-4-yl, we adopted an efficient
(Scheme 2; Ar = 4-F-2-OMe-Ph),
9
two-step intramolecular cyclization strategy similar to that previously reported
2a-d,8a
which enabled delineation of C4 scope as the penultimate step. Hence, Sonogashira couping between a commercially
available alkyne (12) and halide (13) followed by cyclisation under basic conditions afforded first 14 and then 15 in
high yields. In contrast to precedented work, we did not explore the possibility of executing these reactions as part of a
1
0
one-pot procedure. Alternatively, 12 and related alkynes were prepared via Gilbert-Seyferth homologation using the
Ohiro-Bestmann reagent. Suzuki-Miyaura coupling then afforded 8, while subsequent Miyaura borylation using
11
12
nd
either Pd(dppf)Cl
2
or XPhos 2 Generation Precatalyst failed to deliver appreciable amounts of pinacol borate ester
Based on HPLC analysis, des-chloro 15 was the dominant byproduct in all attempted borylation
reactions, and yields of desired product were typically <10% as a mixture of BPin ester and boronic acid (not shown).
13
(
BPin) 16.

8: c
a
b
16: d
1
2
13
14
15
8
1
, R = 4-F-2-OMe-Ph
6, R = BPin
nd
Scheme 2. a) Pd(PPh
3 2 2 3 2 2 3
) Cl , CuI, Et N, ACN, 75 °C, 81%; b) KOtBu, NMP, 97%; c) XPhos 2 Generation Precatalyst, ArB(OH) , Cs CO ,
nd
dioxane/H O, 100 °C, 87%; d) Pd(dppf)Cl or XPhos 2 Generation Precatalyst, B Pin , KOAc, dioxane, 100 °C.
2 2 2
2
The route depicted in Scheme 2 overcame many of the challenges inherent in Scheme 1, because it was more
functionally tolerant with the absence of hydrogenation and indole deprotection steps. This resulted in a shortened
overall reaction sequence. A drawback was the early introduction of the C2 moiety, and alkynes which could not be
purchased required a custom synthesis from related aldehyde or alcohol precursors. Additionally, a consequence of
unsuccessful borylation was that we were unable to easily capitalize on commercial aryl halides as C4 Suzuki-
Miyaura coupling partners without additional functional group manipulation.
We undertook two parallel approaches to develop improved methods to prepare 16. The first was a two-tier catalyst
screening approach for the borylation of 15, which first varied catalyst, ligand, solvent, and base, and analyzed
1
4
reaction progress after 24 hours by HPLC. The best conditions for the initial iteration (See Supplemental) based on
yield and relative levels of des-chloro byproduct (Ar-H) were found to be Pd(dppf)Cl , KOAc, and DMA (yield:
4%). Conditions similar to those in the literature (CyJohnPhos, Pd(OAc) , KOAc, dioxane, 90 °C) were also
2
6
2
successful (yield: 57%) but gave much higher levels of Ar-H. Potassium acetate was a superior base compared to
triethylamine or potassium phosphate. Polar aprotic solvents also minimized Ar-H formation compared to non-polar
solvents such as dioxane, with cyclopentylmethyl ether (CPME) being the exception.
Using this data, a second screening iteration was designed, and results are shown in Table 1. In general, electron-
rich bulky monophosphine ligands such as as dppf, dippf, and Buchwald ligands gave more favorable reaction
profiles. Presumably this was through the promotion of both oxidative addition to the challenging heteroaryl-chloride
bond and rapid reductive elimination due to steric bulk, thereby reducing the potential for formation of des-chloro
byproduct. Pd
active catalytic species arising from dibenzylideneacetone (dba) participation.
2 3 2
dba performed poorly compared to Pd(OAc) , and this may have resulted from formation of a less
1
5
a,b,c,d
Table 1. Unisolated screening yields for the conversion of 15 to 16 based on HPLC analysis after 24 hours at 90 °C.
Catalyst +
Ligand
Solvent
DMA
DMF
Base
KOAc
KOAc
KOAc
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
54
80
75
65
38
61
56
49
62
79
84
56
44
62
64
40
68
78
70
56
55
8
37
57
40
35
39
43
40
46
0
3
1
3
3
5
3
3
27
49
27
57
38
43
29
87
31
24
22
69
36
27
26
79
67
57
71
29
53
40
48
26
70
64
71
29
40
35
41
19
35
16
0
63
78
84
40
57
38
64
27
10
28
16
5
NMP
6
CPME
DMA
DMF
19
1
2
1
NMP
29
10
3
2
CPME
3
8
a
Based on calibration against an internal standard.
b
c
Reactions (n = 1) were performed in 2 mL vials in a 96-well plate format in an inerted glovebox (<5 ppm O
See Supplemental for full details on yield calculations, procedures, and abbreviations. Errors for yields were not calculated, and values
2
2
and <1 ppm H O).
were rounded to whole numbers. As such, results should be used as a guide only.
d
Color coding based on yields (% of Ar-BPin):
< 25
26 - 40
41-60
61-75
76-100
The highest yield was measured using Pd(OAc)
7%). This compared favorably to literature conditions tested in the first screening iteration. Similar yields were also
obtained with: a) Pd(OAc) /PCyPh and KOAc in NMP (yield: 85%) and b) 10 mol% Pd(dppf)Cl and KOAc in NMP
yield: 84%). When testing Pd(OAc) /CyJohnPhos/NaOAc in CPME on moderate scale in a fume hood (See
2
/CyJohnPhos in combination with NaOAc and CPME (yield:
8
2
2
2
(
2
Supplemental) rather than a glovebox, 16 was isolated in only 31% yield. However, purification of 16 was not wholly
successful under normal phase conditions using combinations of solvents such as methanol in dichloromethane or
ethyl acetate, and the final product was contaminated with 16 wt% Ar-H. Preparative reverse phase purification using
acetonitrile in water containing either 0.1% formic acid or 0.1% ammonium hydroxide was not attempted due to
evidence of partial hydrolysis to the corresponding boronic acid under analytical UPLC conditions. While crude

mixtures containing Ar-BPin contaminated with small amounts of Ar-H or boronic acid could be used in subsequent
Suzuki couplings without further purification, we preferred to develop alternative methods to access 16.
Our second strategy to access 16 was predicated on the use of a more reactive bromide. It should be noted that the
-bromo-3-iodo analog of 13 was not pursued because of a) a lack of commercial availability and b) a view that
4
additional steps to prepare such a compound would make the synthesis overlong. Miyaura borylation of a bromide
such as 5 had been previously reported , however, the resulting product contained both undesired olefin and tosyl
2a-c
2e-f
groups. We therefore first removed the tosyl-protecting group of 5 to afford 17 . Deprotonation with sodium
hydride was then followed by transmetalation and lithium-halogen exchange with n-butyllithium; quenching with
Using sodium hydride to first remove the
2
isopropyl pinacol borate afforded 18 cleanly and in good yield.
b
16
azaindole NH allowed for controlled lithium-halogen exchange and avoided self-quenching.
a
b
c
5
17
18
16
d
1
9
Scheme 3. a) NaOH, dioxane, 60 °C, 95%; b) NaH, nBuLi, iPrOBPin, THF, 5 °C then -78 °C to r.t., 75%; c) H
C, 100%; d) H (H-Cube®), 5 wt% Pt on Al (30 mm cartridge), EtOAc, 1 mL/min, 50 °C, see text.
2
, 10 wt% Pd/C, MeOH, 55
°
2
2 3
O
Gratifyingly, hydrogenation of 18 using atmospheric hydrogen at 55 °C afforded 16 in quantitative yield. We
additionally explored reduction of 17 using a ThalesNano Nanotechnology, Inc., H-Cube® and identified conditions
See Supplemental) which led to olefin reduction in the presence of the C4 bromide to provide 19 in approximately
0% yield based on NMR analysis of the crude reaction mixture. While this transformation is notable because both
(
3
olefin and bromide are not typically considered to be orthogonal, we were unable to improve this yield, and, as
anticipated, des-bromo 17 and 19 were major byproducts.
Concurrently we developed a more accessible two-step oxidation-halogenation strategy for preparing 4-bromo-2-
piperidin-4-yl)-7-azaindoles (Scheme 4) based on precedented work for generating C4-bromides from 7-azaindole-7-
(
8a,17
oxides . We were attracted to this methodology because it allowed us to use the concise cyclization chemistry of
Scheme 2 while avoiding indole deprotection and olefin reduction steps. In short, Boc piperidine 21 was prepared
starting from 2-amino-3-iodopyridine 20 (~$25/g; Manchester Organics, cat# R10961) and alkyne 12 (~$45/g;
Melrob, CAS#104839-06-0) in good yield over two steps (53-61%) on 47 g scale. Oxidation with mCPBA then
smoothly afforded N-oxide 22, which was brominated using ammonium bromide in the presence of methanesulfonic
anhydride at -5 °C to provide 19. Overall yields for this four-step sequence were 35-40%, and bromide 19 was then
smoothly converted to 16 using the aforementioned conditions.
a,b
c
d
e
1
6
2
0
21
22
19
Scheme 4. a) 12, Pd(PPh
(CH SO O, NH Br, DME/DMF, -5 °C to r.t., 74%; e) NaH, nBuLi, iPrOBPin, THF, 5 °C then -78 °C to r.t., 72%.
3 2 2 3
) Cl , CuI, Et N, MeCN, 75 °C, 77-89%; b) KOtBu, DMF, 69%; c) mCPBA, EtOAc/DCM, 0 °C to r.t., 89%; d)
3
2
)
2
4
2
To our knowledge, this is the first time 18 has been prepared directly from 17 rather than chloride 16 and the first
b
2
a-c
borylation of 17 without protection of the indole nitrogen . Additionally, hydrogenations of 17 and 18 to afford 19
and 16, respectively, are also unprecedented, as prior work has either necessitated an unsaturated piperidine or
2-3
involved reaction sequences similar to Scheme 2 where an olefin was never present.
Schemes 3 and 4 were also robust, and Scheme 4 is the first reported syntheses of bromide 19.
Borylation conditions of
18
In summary, we adapted precedented chemistries for the late stage diversification of C2 and C4 positions of 2,4-
disubstituted 7-azaindoles. Where C2 diversification was desired, N-tosyl protected iodide intermediates such as 10
enabled rapid exploration via cross-coupling or deprotonation chemistries. An alternative two-step cyclization
strategy which fixed C2 substitution early on enabled C4 diversification from an aryl chloride as the final step. While
shorter, this method failed in our hands to realize adequate quantities of pure BPin 16 from choride 15, limiting our
ability to access halogen-containing coupling partners for SAR exploration.
A two-tiered catalyst screening approach identified improved methods for generating 16 with minimal formation of
des-chloro byproduct. Highest yields were obtained using CPME, which is a green alternative to solvents such as

dioxane, THF, and MTBE. We also adapted conditions for preparing 16 via sequential borylation and hydrogenation
of known bromide 17. Building on this work, we implemented a two-step oxidation/bromination methodology to
prepare bromide 19 on scale in 35-40% yield, and borylation of this material under basic conditions also afforded
desired 16 in good yield. As a whole, this work contributes to the synthesis of 4-substituted 2-(piperidin-4-yl)-7-
azaindoles by expanding available methods for Miyaura borylation of chloride 15 and disclosing the preparation of a
versatile bromide alternative.
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1
2
.
.
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7
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1
2. Ishiyama, T.; Murata, M; Miyaura, N. J. Org. Chem. 1995, 60, 7508-7510.
3. Since the time of this work, conditions have been reported for the conversion of 15 to 16 using CyJohnPhos and Pd(OAc) in
2
dioxane but yields were not reported. See references 2a & 2c.
4. See Supplmental for full details on both initial and follow-up screening results, as well as a Table depicting %Ar-H relative to an
internal standard for each reaction in Table 1.
1
1
1
5. Amatore, C.; Jutand, A.; Khalil, F.; M’Barki, M. A; Mottier, L. Organometallics, 1993, 12, 3168-3178.
6. For references detailing the preparation of C4 boronic acids from C4 bromides of unsubstituted indole and 7-azaindole using
NaH and nBuLi, see reference 5 and: Noronha, G.; Barrett, K.; Cao, J.; Gritzen, C.; Gong, X.; Hood, J.; Mak, C. C.; Mcpherson,
A.; Pathak, V. P.; Renick, J.; Soll, R.; Splittgerber, U.; Wrasidlo, W.; Zeng, B.; Zhao, N.; Dneprovskaia, E. WO 2005096784 A2,
October 20, 2005.
1
1
7. For representative oxidation-bromination of C2-substituted 7-azaindoles in excellent yield, see: a) Adams, N. D.; Adams, J. L.;
Burgess, J. L., Chaudhari, A. M.; Copeland, R. A.; Donatelli, C. A.; Drewry, D. H.; Fisher, K. E.; Toshihiro, H.; Hardwicke, M.
A.; Huffman, W. F.; Koretke-Brown, K. K.; Lai, Z. V.; McDonald, O. B.; Nakamura, H.; Newlander, K. A.; Oleykowski, C. A.;
Parrish, C. A.; Patrick, D. R.; Plant, R.; Sarpong, M. A.; Sasaki, K.; Schmidt, S. J.; Silva, D. J.; Sutton, D.; Tang, J.; Thompson,
C. S.; Tummino, P. J.; Wang, J. C.; Xiang, H.; Yang, J.; Dhanak, D. J. Med. Chem. 2010, 53 (10), 3973-4001.
8. For synthesis of the 4-bromo-5-chloro analog of 19, which starts from commercially available 4-bromo-5-chloro-3-iodo 2-
aminopyridine and uses a method analogous to that of Scheme 2, see references 2a & 2c.

Graphical Abstract (for review)
General methods for the synthesis and late-stage diversification of
Leave this area blank for abstract info.
2
,4-substituted 7-azaindoles.
a,
b,
c
b
b
b
b
a
Jeffrey G. Varnes , Thomas McGuire , Rebecca E. Meadows , Bernard Barlaam , Jemma Clark , Calum R. Cook , Gemma Davison , Chris De Savi ,
b
b
a
a
b
a
b
b
b
Allan Dishington , Craig Donald , Tyler Grebe , Sudhir Hande , Janet Hawkins , Alexander W. Hird , Jane Holmes , Andrew Lister , Simon Lucas , Jane
b
b
b
b
b
c
b
a
b
a
Moore , Esther Moore , Anil Patel , Kurt G. Pike , Bryan Roberts , Andrew Stark , Darren Stead , Kumar Thakur , Paul Turner , Melissa Vasbinder , Bin
a
Yang .
3
4
5-40%
steps

*Highlights



Methods for preparing 2,4-substituted 7-azaindoles are compared.
An iterative catalyst screen was used to optimize borylation conditions.
A scalable synthesis of 4-bromo-2-(piperidin-4-yl)-7-azaindole is described.