A convenient palladium-catalyzed azaindole synthesis

Article abstract of DOI:10.1055/s-0034-1379492

A one-pot protocol is described which allows direct access to azaindoles from amino-halopyridines and ketones.

Full text of DOI:10.1055/s-0034-1379492

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 197–200
197
letter
Synlett
R. De Gasparo et al.
Letter
A Convenient Palladium-Catalyzed Azaindole Synthesis
R2
Raoul De Gasparoa
Philipp Lustenbergera
Christian Mathesa
Thierry Schlamaa
X
cat. Pd
O
R1
N
R3
N
NH
R3
N
Gemma E. Veitch*a
R1
R2
Jacques J. M. Le Paihb
X = Br, Cl
a
Novartis Pharma AG, Novartis Campus, CH-4056 Basel,
Switzerland
+
4
1
6
(
1
6
)
9
6
2
7
1
1
gemma.veitch@novartis.com
b
Johnson Matthey Chiral Technologies, Johnson Matthey
Catalysts, 28 Cambridge Science Park, Milton Road,
Cambridge, CB4 0FP, UK
Received: 30.09.2014
Accepted after revision: 13.10.2014
Published online: 14.11.2014
preferentially. Interestingly the use of the XPhos first-gen-
eration catalyst yielded this product as a single regioisomer,
likely via the alternate order of chemical reactions – that is,
DOI: 10.1055/s-0034-1379492; Art ID: st-2014-d0826-l
ketone arylation followed by enamine formation (Scheme 1,
Abstract A one-pot protocol is described which allows direct access to
azaindoles from amino-halopyridines and ketones.
eq. 2).5
Although both reaction pathways described in Scheme 1
3
a,e
have been described previously, there is only a single ex-
ample that uses a nonsymmetrical alkyl ketone3e and, in
this example, higher loadings of palladium catalyst were re-
quired (20 mol%). We therefore decided to examine wheth-
er the catalyst system identified (Scheme 1, eq. 2) could
provide a general approach to azaindole synthesis using
various alkyl-substituted ketones.
Key words microwave, palladium catalysis, ketone arylation, cycliza-
tion, azaindoles
The azaindole core has generated growing interest
1
within the medicinal chemistry community and thus there
have been significant efforts to improve access to these
2
compounds in recent years. However, there are still limited
3
methods available to prepare azaindoles. Many of the es-
First, the reaction of a range of 2-amino-3-halopyridine
derivatives 1 with acetone was investigated (Table 1). Pleas-
ingly, the reaction worked equally well with both bromide
(1a) and chloride (1b) derivatives (Table 1, entries 1 and 2).
Furthermore, unsubstituted 2-amino-3-bromopyridine
(1c) could be successfully converted into the target 7-azain-
dole (Table 1, entry 3), although a longer reaction time was
required. A tert-butyldiphenylsilyl protecting group (Table
1, entry 4) did not survive the reaction conditions, and only
the 2-amino-3-bromopyridine (1c) and product 2b could
be observed by LC–MS. The same was true in the case of the
tert-butoxycarbonyl protecting group (Table 1, entry 5).
The reaction conditions were then applied to a range of
different ketones (Table 2) using 2-aminobenzyl-3-bromo-
pyridine 1a as the test substrate.
In the case of 2-methyl levulinate the 7-azaindole syn-
thesis proceeded smoothly to provide product 3a in accept-
able yield (Table 2, entry 1). For the unsymmetrical ketones
2-pentanone and 4-methylpentan-2-one (Table 2, entries 2
and 3) the products 3b and 3c were prepared in good yield;
in these cases the excess ketone could be successfully re-
moved in vacuo. In the case of a more sterically hindered
ketone, 3,3-dimethylbutan-2-one (Table 2, entry 4), a mod-
tablished methods used to prepare indoles work poorly
when applied to azaindoles.
We were interested in an efficient method to access the
compound described in Scheme 1 (eq. 1), which is a poten-
tial precursor to a development candidate in the Novartis
pipeline. It was supposed that such a 7-azaindole derivative
could be prepared by a reaction cascade involving enamine
formation followed by intramolecular Heck reaction using a
2
-amino-3-halopyridine and a substituted ketone as sub-
3
a,b,g
strates (Scheme 1).
With the goal of effecting the reac-
tion type described in Scheme 1 (eq. 1), a screen of palladi-
um-based catalyst systems and reaction conditions was
4
carried out. In general, reactivity was very low and only
the starting 2-amino-3-halopyridine or the des-halo deriv-
ative were observed by LC–MS. The only experiments to
provide modest conversion into 7-azaindoles were those in
which the substituted ketone, in this case methyl levulinate,
4
was used as the reaction solvent. Using a catalyst described
3a
in the literature to effect such azaindole syntheses, namely
bis(tri-tert-butylphosphine)palladium(0), mixtures of the
two products described in Scheme 1 (eq. 1 and 2) were ob-
served, with the product of eq. 2 (Scheme 1) being formed
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 197–200

1
98
Synlett
R. De Gasparo et al.
Letter
O
OMe
O
O
X
X
N
OMe
4
OMe
3
a
3
5
2
(1)
O
N
NH
N
6
N 1
N
7
SO2Me
F3C
SO2Me
F3C
SO2Me
isomerization,
Heck reaction
F3C
O
OMe
O
X
O
OMe
OMe
O
(2)
N
NH
O
N
NH
N
N
SO2Me
F3C
X = halogen
SO2Me
F3C
SO2Me
F3C
Scheme 1 (1) Targeted 7-azaindole synthesis with methyl levulinate. (2) Observed 7-azaindole synthesis with methyl levulinate. Reagents and condi-
tions: MgSO , methyl levulinate, K PO (3 equiv), Xphos first-generation catalyst (4 mol%), AcOH (1 equiv), 140 °C, 18 h.
4
3
4
Table 1 Synthesis of 7-Azaindole Products 2a
ketone) is slower for an ethyl ketone compared to a methyl
ketone and therefore the dehalogenation pathway becomes
X
competitive.6
N
N
NH
R
O
N
Table 2 Synthesis of 7-Azaindole Products 3a
R
1
2
R2
Br
Entry
2-Amino-3-halo-pyri- Reaction
7-Azaindole
product
Isolated yield
(%)
R1
b
dine derivative
time (h)
N
N
N
NH
1
2
3
4
1a R = Bn, X = Br
1b R = Bn, X = Cl
1c R = H, X = Br
6
2a R = Bn
2a R = Bn
2b R = H
80
79
59
–
6
1a
3
48
1d R = TBDPS, X = Br 48
1e R = Boc, X = Br 48
2c R = TBDPS
2d R = Boc
Entry Ketone substrate
7-Azaindole product
Reac-
tion
Isolated
yield (%)
5
–
time
a
Reaction conditions: 2-amino-3-halopyridine derivative (1.9 mmol), Mg-
(1715 mg), acetone (7.5 mL), AcOH (1.9 mmol), K PO (3.8 mmol),
(
h)
SO
4
3
4
chloro(2-dicyclohexylphosphino-2′,4′6′-triisopropyl-1,1′-biphenyl)[2-(2-
1
1
O
3a R = CH
2
CH
2
CO
2
Me,
2
73
aminoethyl)phenyl]palladium(II) (0.076 mmol), 140 °C.
2
R = H
b
Single regioisomer.
OMe
O
1
2
2
3
4
3b R = n-Pr, R = H
6
6
83
83
65
erate yield of the product 3d could also be obtained al-
though the reaction required longer to reach completion
O
O
O
(16 h). Acetophenone (Table 2, entry 5) also provided the
1
2
3c R = i-Bu, R = H
expected product 3e in acceptable yield.
Two examples were tested containing an ethyl rather
than a methyl ketone (Table 2, entries 7 and 8). In both cas-
es these reactions did provide some of the desired product
1
2
3d R = t-Bu, R = H
16
(
3g 26% and 3h 28% yield); however, a major byproduct in
these cases was the dehalogenated starting material 1a.
Presumably the first step in the process (α-arylation of the
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 197–200

1
99
Synlett
R. De Gasparo et al.
Letter
Table 3 Synthesis of Other Azaindole Regioisomersa
Entry Ketone substrate
7-Azaindole product
Reac-
tion
time
Isolated
yield (%)
Entry
1
Substrate
Target product
Isolated yield (%)
(
h)
Br
59
1
2
5
O
O
3e R = Ph, R = H
16
73
N
N
N
NH2
NH2
H
1
4
c
2b
2
3
N
0
1
6
7
O
3f R = CH
2
CO
2
Me,
6
59
26
2
R = H
N
H
N
Br
Br
O
a
5
a
1
2
O
O
3g R = Ph, R = Me
48
NH2
28
26
N
N
H
5
b
N
1
2
8
3h R = Me, R = Me
16
28
4b
4
Br
NH2
a
7
N
Reaction conditions according to general procedure A: 2-amino-3-ha-
(1715 mg), ketone (7.5 mL),
(3.8 mmol), chloro(2-dicyclohexylphosphino-
′,4′6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)
0.076 mmol), 140 °C.
N
H
lopyridine derivative (1.9 mmol), MgSO
AcOH (1.9 mmol), K PO
2
4
5c
3
4
N
4
c
(
a
Reaction conditions (entries 2–4): Compound 2b was prepared using
general procedure A,7 compounds 4a–c were subjected to the conditions
described in general procedure B:7 amino-3-halo pyridine derivative (1.5
4 3 4
mmol), MgSO (1354 mg), acetone (5.9 mL), AcOH (1.5 mmol), K PO (3.0
mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-bi-
phenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.06 mmol), 140 °C, 48 h.
Finally, attention was turned towards the synthesis of
other azaindole regioisomers from the corresponding ami-
no-bromopyridines 4. As described previously in Table 1,
the 2-amino-3-bromopyridine provided the target product
2b in modest yield (59%). However, in the case of 2-bromo-
3-aminopyridine 4a only dimerization of this starting ma-
terial could be detected (LC–MS), presumably due to the
propensity of the 2-bromo substituent to undergo substitu-
tion. Pleasingly, the other regioisomers tested (Table 3, en-
tries 3 and 4) did lead to the expected products 5b and 5c
albeit in lower yields than for the 7-azaindole derivative 2b.
In summary, the procedure described herein allows for
rapid and convenient access to a variety of 2-substituted 7-
azaindole derivatives in good yield from methyl ketones
and 2-amino-3-halopyridines. Two examples of 2,3-substi-
tuted 7-azaindoles could also be prepared using this meth-
odology, albeit in lower yield. Other regioisomeric bromo-
aminopyridines were tested under the standard reaction
conditions, providing both 5- and 6-azaindole derivatives.
References and Notes
(
1) For examples of azaindoles exhibiting biological activity, see:
a) Prudhomme, M. Eur. J. Med. Chem. 2003, 38, 123. (b) Walker,
S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109,
080. (c) Blaazer, A. R.; Lange, J. H. M.; van der Neut, M. A. W.;
(
3
Mulder, A.; den Boon, F. S.; Werkman, T. R.; Kruse, C. G.;
Wadman, W. J. Eur. J. Med. Chem. 2011, 46, 5086. (d) Sandham,
D. A.; Arnold, N.; Aschauer, H.; Bala, K.; Barker, L.; Brown, L.;
Brown, Z.; Budd, D.; Cox, B.; Docx, C.; Dubois, G.; Duggan, N.;
England, K.; Everett, B.; Furegati, M.; Hall, E.; Kalthoff, F.; King,
A.; Leblanc, C. J.; Manini, J.; Meingassner, J.; Profit, R.; Schmidt,
A.; Simmons, J.; Sohal, B.; Stringer, R.; Thomas, M.; Turner, K. L.;
Walker, C.; Watson, S. J.; Westwick, J.; Willis, J.; Williams, G.;
Wilson, C. Bioorg. Med. Chem. 2013, 21, 6582. (e) Lee, H. Y.; Pan,
S. L.; Su, M. C.; Liu, Y. M.; Kuo, C. C.; Chang, Y. T.; Wu, J. S.; Nien,
C. Y.; Mehndiratta, S.; Chang, C. Y.; Wu, S. Y.; Lai, M. J.; Chang, J.
Y.; Liou, J. P. J. Med. Chem. 2013, 56, 8008. (f) Cheve, G.; Dayde-
Cazals, B.; Fauvel, B.; Bories, C.; Yasri, A. WO 2014102377 A1
Acknowledgment
We would like to acknowledge Dr Fabrice Gallou for helpful discus-
sions in the preparation of this manuscript.
2
0140703, 2014. (g) Dodd, R.; Cariou, K.; Gourdain, S.; Delabar,
J. M.; Janel, N.; Rodrigues, L. F.; Dairou, J.; Denhez, C. WO
014096093, A1 20140626, 2014.
2) For selected reviews on the synthesis of azaindoles, see:
a) Popowycz, F.; Routier, S.; Mérour, J.-Y.; Joseph, B. Tetrahe-
2
(
Supporting Information
(
dron 2007, 63, 1031. (b) Song, J. J.; Reeves, T. J.; Gallou, F.; Tan,
Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379492.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(c) Mérour, J.-Y.; Routier, S.; Suzenet, F.; Joseph, B. Tetrahedron
2013, 69, 4767.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 197–200

2
00
Synlett
R. De Gasparo et al.
Letter
(
3) For selected examples of azaindole synthesis, see: (a) Nazaré,
nitrogen twice, and heated at 140 °C for 48 h. The reaction
mixture was filtered through silica washing with acetone fol-
lowed by 20% MeOH in acetone. Concentration in vacuo pro-
vided the crude product that was purified as described in the
Supporting Information or below. Selected examples of azain-
doles prepared:
M.; Schneider, C.; Lindenscmidt, A.; Will, D. W. Angew. Chem.
Int. Ed. 2004, 43, 4526. (b) Lachance, N.; April, M.; Jolzy, M. A.
Synlett 2005, 2571. (c) Fang, Y. Q.; Yuen, J.; Lautens, M. J. Org.
Chem. 2007, 72, 5152. (d) de Mattos, M. C.; Alatorre-Santamaria,
S.; Gotor-Fernandez, V.; Gotor, V. Synthesis 2007, 2149.
(e) Spergel, S. H.; Okoro, D. R.; Pitts, W. J. Org. Chem. 2010, 75,
Methyl
3-(1-Benzyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propa-
5316. (f) Whelligan, D. K.; Thomson, D. W.; Taylor, D.; Hoelder,
noate (3a)
S. J. Org. Chem. 2010, 75, 11. (g) Majumdar, K. C.; Ganai, S.;
Chattopadhyay, B.; Ray, K. Synlett 2011, 2369. (h) Knapp, J. M.;
Zhu, J. S.; Tantillo, D. J.; Kurth, M. J. Angew. Chem. Int. Ed. 2012,
Prepared following general procedure A, starting from N-
benzyl-3-bromopyridin-2-amine (1a) and methyl levulinate.
The reaction required 2 h heating at 140 °C. Purification by flash
chromatography (20% tert-butyl methyl ether in heptanes,
51, 10588. (i) Frischmuth, A.; Knochel, P. Angew. Chem. Int. Ed.
2
013, 52, 10084. (j) Leboho, T. C.; van Vuuren, S. F.; Michael, J.
R = 0.18) followed by trituration with 2-methyl pentane gave
the product as a white powder (406 mg, 73%). H NMR (400
f
1
P.; de Koning, C. B. Org. Biomol. Chem. 2014, 12, 307.
4) See Supporting Information for details of the initial screening
experiments performed.
(
(
MHz, CDCl ): δ = 2.69 (obs. t, J = 7.6 Hz, 2 H), 3.00 (obs. t, J = 7.6
3
Hz, 2 H), 3.68 (s, 3 H), 5.59 (s, 2 H), 6.27 (s, 1 H), 7.02–7.09 (m, 3
5) When the 7-azaindole synthesis described in Scheme 1 was
tested with acetone as solvent instead of methyl levulinate, the
mass of the α-arylacetone could be detected by LC–MS (8%)
along with 89% of the cyclized 7-azaindole product. Attempts to
isolate this material via silica gel chromatography led to cycliza-
tion to the 7-azaindole.
H), 7.19–7.29 (m, 3 H), 7.85 (dd, J = 7.8, 1.5 Hz, 1 H), 8.29 (dd,
13
J = 4.6, 1.6 Hz, 1 H). C NMR (101 MHz, CDCl ): δ = 22.2, 32.2,
3
44.8, 51.8, 97.3, 116.0, 120.3, 126.4, 127.3, 127.6, 128.7, 137.9,
+
140.0, 142.2, 148.6, 172.7. LC–MS: m/z [M + H] calcd for
+
C18H19N O : 295.1; found: 295.1.
2
2
1-Benzyl-2-isobutyl-1H-pyrrolo[2,3-b]pyridine (3c)
(
6) In the following paper on α-arylation of ketones there is a pref-
erence for arylation at the less hindered site, see: Fox, J. M.;
Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
Prepared following general procedure A, starting from N-
benzyl-3-bromopyridin-2-amine (1a) and 4-methylpentan-2-
one. The reaction required 6 h heating at 140 °C under micro-
wave irradiation. Purification by flash chromatography (5%
1360.
(
7) General Procedure A
EtOAc in heptanes, R = 0.14) gave the product as an off-white
f
1
To a microwave vial equipped with a magnetic stirrer was
added 2-amino-3-halo pyridine derivative (1.9 mmol, 1 equiv),
MgSO4 (1715 mg), ketone (7.5 mL), and AcOH (0.109 mL, 1.9
mmol, 1 equiv). The reaction was purged with argon under stir-
ring for 10 min at 22 °C. Then K PO (807 mg, 3.8 mmol, 2
solid (418 mg, 83%). H NMR (400 MHz, CDCl ): δ = 0.95 (d,
3
J = 6.8 Hz, 6 H), 1.94 (obs. septet, J = 6.8 Hz, 1 H), 2.53 (dd,
J = 6.8, 0.8 Hz, 2 H), 5.57 (s, 2 H), 6.28 (obs. s, 1 H), 6.98–7.03 (m,
2 H), 7.06 (dd, J = 7.7, 4.6 Hz, 1 H), 7.18–7.28 (m, 3 H), 7.85 (dd,
13
J = 7.7, 1.6 Hz, 1 H), 8.26 (dd, J = 4.8, 1.5 Hz, 1 H). C NMR (101
3
4
equiv) and chloro(2-dicyclohexylphosphino-2′,4′6′-triisopro-
pyl-1,1′biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (56
MHz, CDCl ): δ = 22.6, 27.8, 36.2, 44.8, 98.5, 115.9, 120.5, 126.3,
3
127.1, 127.2, 128.6, 138.3, 141.1, 141.7, 148.5. LC–MS: m/z [M +
+
+
mg, 0.076 mmol, 0.04 equiv) were added. The vial was closed,
purged with argon under stirring for 10 min at 22 °C, and
heated to 140 °C. Upon completion, the reaction mixture was
filtered through silica that was subsequently rinsed with EtOAc.
Concentration in vacuo provided the crude product which was
purified as described in the Supporting Information or below.
General Procedure B
H] calcd for C18H21N2 : 265.2; found: 265.2.
1-Benzyl-3-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (3g)
Prepared following general procedure A, starting from N-
benzyl-3-bromopyridin-2-amine (1a) and propiophenone. The
reaction required 48
h heating at 140 °C. Purification by
reverse-phase flash chromatography (50% MeCN in H O to 100%
2
MeCN; R = 0.26, MeCN–H O = 8:2) gave the product as an
f
2
1
To a hydrogenation vial flushed with argon was added 2-amino-
orange oil (150 mg, 26%). H NMR (400 MHz, CDCl ): δ = 2.25 (s,
3
3-halo pyridine derivative (1.5 mmol, 1 equiv), MgSO4 (1354
3 H), 5.44 (s, 2 H), 6.84–6.88 (m, 2 H), 7.08–7.15 (m, 4 H), 7.24–
mg), acetone (5.9 mL), AcOH (0.086 mL, 1.5 mmol, 1 equiv),
K PO (637 mg, 3.0 mmol, 2 equiv), and chloro(2-dicyclohexyl-
7.27 (m, 2 H), 7.36–7.41 (m, 3 H), 7.89 (dd, J = 7.8, 1.5 Hz, 1 H),
13
8.35 (dd, J = 4.8, 1.5 Hz, 1 H). C NMR (101 MHz, CDCl ): δ = 9.1,
3
4
3
phosphino-2′,4′6′triisopropyl-1,1′biphenyl)[2-(2-aminoethyl)-
phenyl]palladium(II) (44 mg, 0.06 mmol, 0.04 equiv). The vial
was inserted into the hydrogenation apparatus, purged with
45.8, 107.5, 115.6, 121.2, 126.6, 126.7, 126.8, 128.2, 128.2,
128.3, 130.5, 131.5, 137.7, 138.7, 143.0, 148.4. LC–MS: m/z [M +
+
+
H] calcd for C21H19N2 : 299.2; found: 299.2.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 197–200

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.