One-Pot Coupling-Cyclization-Alkylation Synthesis of 1,2,5-Trisubstituted 7-Azaindoles in a Consecutive Three-component Fashion

Article abstract of DOI:10.1055/s-0036-1590837

1,2,5-Trisubstituted 7-azaindoles are rapidly and efficiently prepared in a one-pot, copper-free alkynylation-cyclization-alkylation sequence starting from unprotected 2-aminopyridyl halides in a consecutive three-component fashion. By extension to a consecutive four-component coupling-cyclization-iodination-alkylation synthesis of 3-iodo-1-methyl-2-phenyl-1 H -pyrrolo[2,3- b ]pyridine, a concise synthesis of SIS3, a selective TGF-β1 and signaling inhibitor, was realized.

Full text of DOI:10.1055/s-0036-1590837

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
T. Lessing, T. J. J. Müller
Letter
Synlett
One-Pot Coupling–Cyclization–Alkylation Synthesis of 1,2,5-Tri-
substituted 7-Azaindoles in a Consecutive Three-component Fash-
ion
Timo Lessing
Rapid
O
coupling-cyclization-alkynylation
Thomas J. J. Müller*
0
0
0
0
0-
0
0
1
9-
8
0
9
7-
2
4
X
synthesis in a one-pot fashion
OMe
OMe
N
N
[Pd(PPh3)2Cl2, (1-Ad)2PBn·HBr]
DBU, DMSO, 100 °C, 1 h
R1
Br
R1
N
+
R2
Ph
R2
Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1,
40225 Düsseldorf, Germany
Me
then: KOt-Bu, DMSO, 100 °C, 0.25 h
then: R3-X (3), DMSO, rt, 5 min
N
R3
N
NH2
N
concise synthesis of
transforming growth factor
TGF-β1 antagonist SIS3
ThomasJJ.Mueller@uni-duesseldorf.de
14 examples (21–65%)
Received: 05.05.2017
Accepted after revision: 20.06.2017
Published online: 24.07.2017
vation (Scheme 1).10 Two compatible bases enable this
efficient transformation, in which 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) is well suited for the alkynyla-
tion step. The employed second base KOt-Bu is by 6–8 pKa
units more basic than DBU,11 both in water (19.0) and in
DMSO (32.2).12 Therefore, the 2-aminopyridine (pKa in DMSO:
27.7)12 will be quantitatively deprotonated to undergo a 5-
endo-dig cyclization and subsequent prototropy to furnish
the corresponding base of the 7-azaindole (with an esti-
mated pKa of 19 in DMSO). Since the reaction medium es-
sentially contains this anion prior to workup, we reasoned
that this strongly nucleophilic intermediate should be per-
fectly suited for concatenating a terminal electrophilic trap-
ping, and thereby furnishing 1,2,5-trisubstituted 7-azain-
doles in a consecutive three-component fashion.
DOI: 10.1055/s-0036-1590837; Art ID: st-2017-b0330-l
Abstract 1,2,5-Trisubstituted 7-azaindoles are rapidly and efficiently
prepared in a one-pot, copper-free alkynylation–cyclization–alkylation
sequence starting from unprotected 2-aminopyridyl halides in a con-
secutive three-component fashion. By extension to a consecutive four-
component coupling–cyclization–iodination–alkylation synthesis of 3-
iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, a concise synthesis
of SIS3, a selective TGF-β1 and signaling inhibitor, was realized.
Key words 7-azaindoles, alkylation, alkynylation, cyclization, multi-
component reaction
The steadily increasing insight into cancer metabolism
has revealed that kinase inhibitors are promising targets1
for identifying and developing privileged scaffolds2 as novel
anticancer agents.3 Among many structures, 7-azaindoles,
i.e., 1H-pyrrolo[2,3-b]pyridines, constitute a particularly in-
teresting biheterocyclic scaffold4 with enormous potency as
kinase inhibitors.5 As a consequence, a steady demand for
synthetic strategies toward 7-azaindoles has become an on-
going evergreen.6 For enhancing library design and thereby
to lead-finding and development, the strategic concept of
multicomponent reactions (MCR),7 i.e., one-pot processes
exploiting the perpetual generation of relative reactivity as
a reactivity based principle in a domino, sequential or con-
secutive fashion,8 has turned out to be particularly favor-
able. Surprisingly, MCR and one-pot syntheses of 7-azain-
dole derivatives have remained relatively unexplored to
date.9
[Pd(PPh3)2Cl2]
[(1-Ad)2PBn·HBr]
DBU, DMSO
100 °C, 1–2 h
R1
Br
R1
R2
N
NH2
then: KOt-Bu, DMSO
N
N
100 °C, 0.25–1.1 h
+
H
R2
19 examples (18–90%)
aqueous
workup
coupling
R2
R1
R1
R2
N
N
N
NH2
deprotonation
prototropy
R2
R1
R1
cyclization
R2
Recently, we reported a copper-free Pd-catalyzed alky-
nylation–cyclization synthesis of 2-substituted 7-azain-
doles in a one-pot fashion starting from 2-amino-3-bro-
mopyridines void of additional nitrogen protection or acti-
N
N
N
NH
H
Scheme 1 One-pot copper-free Pd-catalyzed alkynylation–cyclization
synthesis of 2-substituted 7-azaindoles and tentative mechanistic ratio-
nale
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
T. Lessing, T. J. J. Müller
Letter
Synlett
Upon reaction of 2-amino-3-bromopyridines 1 and ter-
minal alkynes 2 in DMSO at 100 °C for 1–2 h in the presence
of catalytic amounts of Pd(PPh3)2Cl2 and cataCXium® A Bn·HBr
as a ligand,13 the alkynylation product was further reacted
with KOt-Bu at 100 °C for 15 minutes and subsequently
with a trapping electrophile 3 at room temperature for five
minutes to furnish, after aqueous workup and purification,
the 1,2,5-trisubstituted 7-azaindoles 4 in 21–65% isolated
yield (Scheme 2, Table 1).14 The structures of all previously
unreported compounds were unambiguously assigned by
spectroscopic methods (1H NMR and 13C NMR, IR) and by
combustion analysis. The employed three points of diversi-
ty can be substituted alkyl and halide substituents (R1), ali-
phatic and aromatic moieties (R2), and arylmethyl and
functionalized alkyl substituents (R3), and the obtained iso-
lated yields refer to a quite efficient sequence with an aver-
age yield of 59–87% per bond-forming step.
2.50 mol% Pd(PPh3)2Cl2
5.00 mol% (1-Ad)2PBn·HBr
DBU (3.00 equiv)
R1
Br
R1
DMSO, 100 °C, 1 h
R2
R2
+
then: KOt-Bu (4.50 equiv)
DMSO, 100 °C, 0.25 h
then: R3-X (3) (2–4 equiv)
DMSO, rt, 5 min
N
R3
N
NH2
N
1
2
4
Scheme 2 Three-component coupling–cyclization–alkylation synthe-
sis of 1,2,5-trisubstituted 7-azaindoles 4
Table 1 One-Pot, Three-Component Synthesis of 1,2,5-Trisubstituted 7-Azaindoles 4
Entry
1
2-Amino-3-bromopyridine 1
Alkyne 2
Electrophile 3
PhCH2Br (3a)
1,2,5-Trisubstituted 7-azaindole
Yield (%)a
Me
Me
Br
Ph
Ph
N
4a (32)
N
(2a)
N
NH2
(1a)
Ph
Me
Me
Ph
Ph
2
3
1a
2a
MeI (3b)
4b (65)
4c (52)
N
N
N
Me
F
Br
N
1a
2a
2a
(3c)
F
Me
Ph
N
Br
N
4
1a
4d (49)
Br
(3d)
Br
Me
Ph
Br
N
N
N
N
N
N
5
6
1a
1a
2a
2a
4e (27)
Me
(3e)
Me
Me
Ph
F3C
Br
4f (21)
(3f)
F3C
Me
Ph
F
Br
7
1a
2a
4g (65)b
F
F
(3g)
F
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
T. Lessing, T. J. J. Müller
Letter
Synlett
Table 1 (continued)
Entry
2-Amino-3-bromopyridine 1
Alkyne 2
Electrophile 3
1,2,5-Trisubstituted 7-azaindole
Yield (%)a
Br
Ph
8a
2a
3b
4h (57)
4i (34)
N
N
N
(1b)
NH2
Me
Me
Ph
Br
9
1a
1a
1a
2a
2a
2a
N
N
(3h)
Me
Ph
MeO
Br
N
N
10b
4j (34)
4k (38)
OMe
MeO
OMe
(3i)
Me
Ph
MeO
Br
11
N
N
(3j)
MeO
Me
N
N
12
13
14
1a
1a
3c
3c
3c
4l (43)
(2b)
F
Me
nBu
N
N
nBu
4m (28)
(2c)
F
Cl
Ph
Cl
Br
N
N
2a
4n (61)
N
NH2
F
(1c)
a After addition of the electrophile the mixture was stirred at rt for 2.5 h.
b After addition of electrophile 3i the reaction mixture was stirred at 100 °C for 23 h.
OMe
O
The scalability of this novel one-pot three-component
synthesis of 1,2,5-trisubstituted 7-azaindoles as illustrated
for compound 4h encouraged us to probe the concept using
OMe
OMe
OMe
N
O
N
+
Lautens’ final step in the synthesis of SIS3 (Scheme 3),15
a
potent and selective TGF-β1 and signaling inhibitor that
suppresses Smad3 phosphorylation.16 Lautens’ appealing
synthesis uses a terminal Heck reaction of an acrylamide
with a 3-iodo-7-azaindole that is prepared through a domi-
no coupling–cyclization sequence as a key step in a long lin-
ear synthesis consisting of four steps including isolation
and purification operations.
I
Ph
N
N
Ph
Me
N
N
SIS3
Me
Scheme 3 Retrosynthetic analyses of the transforming growth factor
(TGF)-β1 antagonist SIS3 by Lautens
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
T. Lessing, T. J. J. Müller
Letter
Synlett
Therefore, we set out to extend the one-pot coupling–
cyclization–alkylation synthesis of 1,2,5-trisubstituted 7-
azaindoles by an iodination step embedded in the one-pot
scenario. Deviating from the coupling–cyclization–alkyla-
tion protocol (see above), the iodination with N-iodosuc-
cinimide was placed prior to the alkylation, taking advan-
tage of the increased electron density of the anion resulting
from the cyclization (Scheme 4).
scalability of the sequence and its extension to a consecu-
tive four-component coupling–cyclization–iodination–al-
kylation synthesis of 3-iodo-1-methyl-2-phenyl-1H-pyrro-
lo[2,3-b]pyridine allowed a concise synthesis of SIS3 to be
introduced; the latter is a selective TGF-β1 and signaling in-
hibitor that operates by suppressing Smad3 phosphoryla-
tion. Further studies applying the coupling–cyclization–al-
kylation concept to other heterocycles and its application in
the syntheses of complex molecules are currently under
way.
Br
2.50 mol% Pd(PPh3)2Cl2
5.00 mol% (1-Ad)2PBn·HBr
DBU (3.00 equiv)
DMSO, 100 °C, 1 h
I
N
NH2
Ph
1b
Ph
Acknowledgment
then: KOt-Bu (4.50 equiv)
DMSO, 100 °C, 0.25 h
then: N-iodo succinimide (3.00 equiv)
DMSO, rt, 5 h
+
N
N
Me
5 (56%)
The authors cordially thank the Fonds der Chemischen Industrie (sti-
pend for T.L.) for financial support.
2a
then: MeI (3b) (4.50 equiv)
DMSO, rt, 5 min
Scheme 4 Four-component coupling–cyclization–iodination–alkylation
synthesis of 3-iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (5)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590837.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
After addition of methyliodide (3b) to the reaction mix-
ture, the 3-iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyri-
dine (5) was isolated in 56% yield, which represents an av-
erage yield of 87% per bond-forming step. In comparison,
from commercially available Boc-protected 2-amino pyri-
dine Lautens’ four-step synthesis of iodide 5 furnishes an
overall yield of 38%, accounting for an average yield per step
of 79%.
References and Notes
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Kyne, R. E.; Liu, K. K. C.; Fink, S. J.; O’Donnell, C. J. Bioorg. Med.
Chem. 2016, 24, 1937. (b) Welsch, M. E.; Snyder, S. A.; Stockwell,
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(d) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
With iodide 5 in hand, acrylamide 617 was reacted in a
Heck reaction according to Lautens’ conditions15 to give, af-
ter purification, the transforming growth factor TGF-β1 an-
tagonist SIS3 (7) in 53% yield (Scheme 5).
(3) (a) Rathi, A. K.; Syed, R.; Singh, V.; Shin, H. S.; Patel, R. V. Recent
Pat. Anti-Cancer Drug Discovery 2017, 12, 55. (b) Asati, V.;
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I
O
OMe
N
Ph
+
N
N
OMe
Me
5
6
5.00 mol% Pd(OAc)2
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Q.; Phoa, A. F.; Abbassi, R. H.; Hoque, M.; Reekie, T. A.; Font, J. S.;
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Feraud, M.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 2016, 26,
4101. (e) Wucherer-Plietker, M.; Merkul, E.; Müller, T. J. J.;
Esdar, C.; Knochel, T.; Heinrich, T.; Buchstaller, H. P.; Greiner,
H.; Dorsch, D.; Finsinger, D.; Calderini, M.; Bruge, D.; Grädler, U.
Bioorg. Med. Chem. Lett. 2016, 26, 3073. (f) Dayde-Cazals, B.;
Fauvel, B.; Singer, M.; Feneyrolles, C.; Bestgen, B.; Gassiot, F.;
Spenlinhauer, A.; Warnault, P.; Van Hijfte, N.; Borjini, N.; Cheve,
G.; Yasri, A. J. Med. Chem. 2016, 59, 3886. (g) Liu, N.; Wang, Y. F.;
Huang, G. C.; Ji, C. H.; Fan, W.; Li, H. T.; Cheng, Y.; Tian, H. Q.
Na2CO3 (1.00 equiv)
Bu4NCl (1.00 equiv)
DMF, 200 °C (MW), 7 min
O
OMe
N
N
N
OMe
Ph
Me
SIS3 (7) (53%)
Scheme 5 Synthesis of the transforming growth factor TGF-β1 antag-
onist SIS3 (7)
In summary, we have disclosed a practical, efficient and
rapid Pd-catalyzed one-pot coupling–cyclization–alkyla-
tion synthesis of 1,2,5-trisubstituted 7-azaindoles in the
sense of a consecutive three-component fashion. The easy
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
T. Lessing, T. J. J. Müller
Letter
Synlett
Bioorg. Chem. 2016, 65, 146. (h) Baltus, C. B.; Jorda, R.; Marot, C.;
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(b) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y. Tetrahe-
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(14) Typical Procedure for the Synthesis of 1,5-Dimethyl-2-
phenyl-1H-pyrrolo[2,3-b]pyridine (4b): In a dry screw-cap
Schlenk tube with a magnetic stir bar were placed 2-amino-3-
bromo-5-methyl pyridine (1a; 93 mg, 0.50 mmol), Pd(PPh3)2Cl2
(9.0 mg, 13 μmol), and (1-Ad)2PBn·HBr (12 mg, 25 μmol) and
the vessel was evacuated. After flushing the vessel with nitro-
gen, anhydrous DMSO (1.0 mL), the corresponding phenyl acet-
ylene (2a; 61 mg, 0.60 mmol) and DBU (225 mg, 1.50 mmol)
were added and the reaction mixture was stirred at 100 °C
under nitrogen for 1 h until the bromide was completely con-
sumed (reaction monitored by TLC). After cooling to rt KOt-Bu
(253 mg, 2.25 mmol) and DMSO (0.50 mL) were added and the
mixture was stirred at 100 °C under nitrogen for 0.25 h. After
cooling to rt, methyliodide (3b; 142 mg, 1.00 mmol) was added
to the reaction mixture, which was stirred at rt for 5 min. Then,
deionized water or brine (20 mL) was added to the mixture. The
aqueous layer was extracted several times with ethyl acetate or
dichloromethane. The combined organic phases were dried
(anhydrous sodium sulfate) and, after filtration, the solvents
were removed in vacuo. The residue was adsorbed on silica and
purified by chromatography on silica gel (SNAP cartridge 100 g,
hexanes/ethyl acetate) with a Biotage SP-1 flash chromatogra-
phy purification system to give analytically pure 4b as a yellow
solid. Yield: 72 mg (65%); mp 65 °C. IR (ATR): 3119 (w), 3078
(w), 3055 (w), 3005 (w), 2980 (w), 2945 (w), 2916 (w), 1599
(w), 1566 (w), 1532 (w), 1485 (m), 1296 (m), 748 (s), 694
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and Reactions Involving a Carbonyl Compound as Electrophilic
Component, Science of Synthesis; Müller, T. J. J., Ed.; Georg
Thieme Verlag KG: Stuttgart, 2014, 5.
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Mule, Y. B.; Bandgar, B. P. J. Chin. Chem. Soc. (Taipei) 2016, 63,
323. (b) Dongare, S. B.; Chavan, H. V.; Bhale, P. S.; Mule, Y. B.;
Kotmale, A. S.; Bandgar, B. P. Chin. Chem. Lett. 2016, 27, 99.
(c) Vilches-Herrera, M.; Knepper, I.; de Souza, N.; Villinger, A.;
Sosnovskikh, V. Y.; Iaroshenko, V. O. ACS Comb. Sci. 2012, 14,
434. (d) Suresh, R.; Muthusubramanian, S.; Senthilkumaran, R.;
Manickam, G. J. Org. Chem. 2012, 77, 1468. (e) Tasch, B. O. A.;
Merkul, E.; Müller, T. J. J. Eur. J. Org. Chem. 2011, 4532.
(f) Merkul, E.; Schäfer, E.; Müller, T. J. J. Org. Biomol. Chem. 2011,
9, 3139. (g) Merkul, E.; Klukas, F.; Dorsch, D.; Grädler, U.;
Greiner, H. E.; Müller, T. J. J. Org. Biomol. Chem. 2011, 9, 5129.
(h) Sharma, S. K.; Mandadapu, A. K.; Saifuddin, M.; Gupta, S.;
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hedron Lett. 2010, 51, 6022.
(m) cm–1 1H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.86 (s,
.
3 H), 6.44 (s, 1 H), 7.42–7.52 (m, 5 H), 7.70–7.71 (m, 1 H), 8.19
(m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 18.7 (CH3), 30.1 (CH3),
99.0 (CH), 120.7 (Cquat), 125.1 (Cquat), 128.3 (CH), 128.4 (CH),
128.7 (CH), 129.2 (CH), 132.6 (Cquat), 142.1 (Cquat), 143.5 (CH),
148.1 (Cquat). MS (EI, 70 eV): m/z (%) = 223 (15), 222 (100) [M]+,
221 (84), 220 (5), 205 (6), 152 (5), 145 (17) [M-C6H5]+, 111 (7),
110 (11). Anal. calcd. for C15H14N2 (222.3): C 81.05, H 6.35, N
12.60; Found: C 80.92, H 6.07, N 12.40.
(10) Lessing, T.; Sterzenbach, F.; Müller, T. J. J. Synlett 2015, 26, 1217.
(11) (a) Kaupmees, K.; Trummal, A.; Leito, I. Croat. Chem. Acta 2014,
87, 385. (b) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.;
Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
(12) Li, J.-N.; Liu, L.; Fu, Y.; Guo, Q.-X. Tetrahedron 2006, 62, 4453.
(15) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152.
(16) Jinnin, M.; Ihn, H.; Tamaki, K. Mol. Pharmacol. 2006, 69, 597.
(17) Dubs, C.; Hamashima, Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.;
Hashizume, D.; Sodeoka, M. J. Org. Chem. 2008, 73, 5859.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E