Rare-Earth-Metal-Catalyzed Synthesis of Azaindolines and Naphthyridines via C?H Cyclization of Functionalized Pyridines

Article abstract of DOI:10.1002/adsc.201901473

We report herein a rare-earth-metal-catalyzed insertion of a 2-pyridine C(sp²)?H bond into an intramolecular unactivated vinyl bond. This reaction provides streamlined access to a range of azaindolines in moderate to excellent yields. The salient features of this reaction include simple and mild reaction conditions, 100% atom efficiency, and wide substrate scope. This methodology is also used to construct other nitrogen-containing compounds such as naphthyridine derivatives. A plausible mechanism for the formation of azaindolines involving initial C?H bond activation by the lanthanide complex followed by C=C insertion into a Ln?C bond to form an alkyl lanthanide species that subsequently undergoes cyclization is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201901473

Title: Rare-Earth Catalyzed Synthesis of Azaindolines and
Naphthyridines via C-H Cyclization of Functionalized Pyridines
Authors: Pengqing Ye, Yinlin Shao, Fangjun Zhang, Jinxuan Zou,
Xuanzeng Ye, and Jiuxi Chen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901473
Link to VoR: http://dx.doi.org/10.1002/adsc.201901473

10.1002/adsc.201901473
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rare-Earth-Metal-Catalyzed Synthesis of Azaindolines and
Naphthyridines via C-H Cyclization of Functionalized Pyridines
Pengqing Ye,a Yinlin Shao,a,c* Fangjun Zhang,b* Jinxuan Zou,a Xuanzeng Ye,a and
Jiuxi Chena*
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035 (China)
E-mail: shaoyl@wzu.edu.cn; jiuxichen@wzu.edu.cn
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035 (China)
b
E-mail: rjzfj@wmu.edu.cn
Institute of New Materials & Industrial Technology, Wenzhou University, Wenzhou 325035 (China)
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We report herein a rare-earth-metal-catalyzed for the formation of azaindolines involving initial C-H bond
insertion of a 2-pyridine C(sp2)-H bond into an intramolecular activation by the lanthanide complex followed by C=C
unactivated vinyl bond. This reaction provides streamlined insertion into a Ln-C bond to form an alkyl lanthanide
access to a range of azaindolines in moderate to excellent species that subsequently undergoes cyclization is proposed.
yields. The salient features of this reaction include simple and
mild reaction conditions, 100% atom efficiency, and wide
substrate scope. This methodology is also used to construct
other nitrogen-containing compounds such as naphthyridine
derivatives. A plausible mechanism
Keywords: rare-earth-metal catalysis; C-H cyclization;
azaindolines; functionalized pyridine; naphthyridines
Introduction
Figure 1. Azaindolines featured in various drug discovery
programs.
Pyridine-fused
heterocycles
have
received
considerable interest because of their biological
activity, interesting optical properties, and
applications in organometallics that cannot be
achieved by the pyridine skeleton alone.[1] Among
are usually unsuccessful when extended to
azaindolines because of the subtle electronic
perturbations of the pyridine ring.[6] Consequently, the
development of methods to prepare azaindolines is
important for medicinal chemistry and represents a
worthwhile goal in organic synthesis.
numerous
pyridine-fused
hybrid
scaffolds,
azaindolines are of particular importance because of
their prominence in natural products and drug
discovery programs (see Figure 1 for representative
examples).[2] Therefore, the synthesis of diverse
azaindolines has been of long-standing interest in
organic and medicinal chemistry. Compared with the
multiple methods available for the synthesis of
indolines,[3] classical strategies such as Fischer indole
synthesis[4] and the Friedel−Crafts reaction[5]
Synthetic approaches to produce this class of
compounds have hitherto relied on the derivatization
of pre-existing pyridine frameworks to build the
azaindoline skeleton. Many elegant general synthetic
approaches to readily access all four isomers of
azaindolines have been achieved.[7] Methods to
prepare the 7-azaindoline motif include radical
cyclization[8] and base- and metal-mediated
annulations.[9] Synthetic methods to produce 6-
azaindolines[10] and 5-azaindolines[11] have also been
developed. Reports of 4-azaindolines are particularly
scarce, with existing synthetic routes involving
nucleophilic attack of nitrogen onto tosylate or alkenyl
intermediates (Scheme 1A),[12] palladium-catalyzed
C(sp3)–H/C(Ar)–X coupling reactions (Scheme
1B),[13] and a radical cyclization pathway (Scheme
1C).[14] However, in many instances, the practicality of
1
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10.1002/adsc.201901473
Advanced Synthesis & Catalysis
the methods is offset by the low atom economy,
narrow scope, special starting materials, and laborious
workup needed to remove side products. Therefore,
the development of convenient practical methods to
construct azaindolines is still relevant.
To our delight, the NMR yield of 2a increased to 95%
when the reaction temperature was raised to 100 °C
(Table 1, entries 9 and 10). Decreasing the reaction
time and catalyst loading led to a drop of yield (Table
1, entries 11 and 12). The reaction did not work in the
absence of Y[N(SiMe3)2]3 (Table 1, entry 13).
Transition-metal-catalyzed C-H functionalization
of pyridine has become a powerful strategy to
synthesize pyridine derivatives in an energy-efficient
and step-economic fashion.[15] In contrast to late
transition-metal catalysts, lanthanides have played an
important role in this type of transformation because
of their high activity that is observed in the absence of
complex additives and unprecedented types of
reactivity.[16] Inspired by previous work, as part of our
research on rare-earth-metal-catalyzed synthesis of N-
containing heterocycles,[17] we envisioned that a
variety of 4-azaindolines could be synthesized by C-H
cyclization via a pyridine–lanthanide intermediate
with a C=C bond generated in situ (Scheme 1D).
Efficient one-step synthesis of 4-azaindoline skeletons
with 100% atom economy has not been documented in
the literature.
Table 1. Optimization of the reaction conditions for
formation of 2a from 1a.[a]
[a] Reaction conditions: 1a (0.50 mmol), catalyst (x mol%),
solvent (3 mL), N2.
[b]
1
Yield of the crude reaction mixture determined by H
NMR spectroscopy (internal standard: ferrocene).
[c] Isolated yield.
Replacement of Y[N(SiMe3)2]3 with other rare-earth-
metal sources, such as Yb(OTf)3 or YCl3, resulted in
no reaction (Table 1, entries 14 and 15).
With these optimized conditions in hand, we
subsequently explored the substrate scope and
limitations
of
this rare-earth-metal-catalyzed
intramolecular annulative insertion reaction by using
various vinyl-substituted pyridin-3-amines as
substrates for the synthesis of 4-azaindolines. First, the
variation of the pyridine ring was investigated. The
results showed that the electronic effect of the
substituents dramatically affected the yield of this
transformation under the standard conditions. For
example, substrates bearing a methyl group afforded
the cyclized products 2b and 2c in 86% and 91% yield,
respectively (Table 2, entries 1 and 2). Electron-
withdrawing groups such as fluoro, chloro, and bromo
substituents at the 5-position on the pyridine ring were
not well tolerated in this transformation, affording the
desired 4-azaindolines 2d–2f in low yield. In general,
the presence of strongly coordinating atoms on the
substrate had a negative influence on the lanthanide
catalytic reaction because of their competing
coordination with the highly Lewis-acidic Ln3+. For
example, the C-H cyclization reaction of 1g gave
inferior results to those for 1b in the preparation of 4-
azaindolines. However, when the N-benzyl-substituted
Scheme 1. Comparison of prior and current work.
Results and Discussion
With the above-described idea in mind, we initiated
our investigation by attempting to synthesize 1,3-
dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (2a)
from N-allyl-N-methylpyridin-3-amine (1a); the
results are summarized in Table 1. First, five
homoleptic bis(trimethylsilyl)amides of lanthanide
metals were tested by performing the reaction at 80 °C
for 24 h in toluene. Y[N(SiMe3)2]3 was found to be the
best catalyst tested, furnishing the target cyclized
product 2a in 75% NMR yield (Table 1, entries 1–5).
A survey of solvents revealed that hexane was optimal
to give a comparable yield of 70%, whereas the use of
tetrahydrofuran (THF) and 1,2-dichloroethane (DCE)
decreased the yield dramatically (Table 1, entries 6–8).
2
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10.1002/adsc.201901473
Advanced Synthesis & Catalysis
[b]
substrate 1h was tested, this cyclization reaction could
not proceed well under same conditions (Table 2, entry
7).
a Teflon cap under N2, 100 °C, 24 h, isolated yield.
Bn2NH (10 mol%) was added. [c] Bn2NH (10 mol%), 120 °C,
48 h.
To improve the catalytic efficiency of this reaction,
we next investigated various amine additives[18] (see
the Supporting Information) and found that when 10
mol% of Bn2NH was added, the yield of 2h increased
to 87%. Next, we examined the reaction of 1d–1g with
Bn2NH as additive and found that the transformation
afforded the desired products in higher yields, ranging
from 23% to 86%, with the remaining starting material
recovered. Other alkyl groups such as 2-phenylethyl
were compatible with the transformation, affording 2i
in 81% yield (Table 2, entry 8). We also examined N-
aryl substrates; the results demonstrated that the
electronic properties of the substituents affected the
yield to some extent. In general, electron-donating
substituents (e.g., methyl-containing substrates)
provided a low yield (Table 2, entries 9–11). A cyano-
containing substrate was also compatible with this
cyclization protocol, affording the desired product in
37% yield, with remaining 1m recovered (Table 2,
entry 12). Next, we examined the R4 and R5 groups at
the vinyl substituent. The results demonstrated that
both the steric
Table 3. Substrate scope of vinyl-substituted quinoline-
3-amines.[a]
Table 2. Substrate scope of vinyl-substituted pyridin-3-
Reaction conditions: 1 (0.5 mmol), Y[N(TMS)2]3 (10
mol%), toluene (3 mL), Bn2NH (10 mol%), sealed
Schlenk tube equipped with a Teflon cap under N2,
100 °C, 24 h, isolated yield.
amines.[a]
and electronic effects of the substituent influenced the
reaction. For example, when a substrate bearing a
methyl group attached to the proximal carbon of the
vinyl substituent was examined, 2n was obtained in a
lower yield of 72% compared to that of 2j (Table 2,
entry 13). A substrate bearing an electron-withdrawing
phenyl group attached to the terminal carbon of the
linker only afforded 2p in 19% yield under same
conditions, which was much lower than the yields of
2o and 2a (Table 2, entries 14 and 15). Use of N,N-
diallylpyridin-3-amine resulted in a lower yield (Table
2, entry 16).
This rare-earth-metal catalyzed C-H cyclization
reaction can also proceed smoothly to afford
naphthyridine derivatives under modified conditions.
Either a methyl or chloro group at the 5-position of the
pyridine ring decreased the cyclization efficiency to
the naphthyridine skeleton (Table 2, entries 17–22),
possibly because Ln3+ favored the coordinated
configuration of intramolecular γ C=C over δ C=C for
five-membered ring construction. In addition to 1,1-
disubstituted alkenes, compound 1x did not undergo
the transformation under current conditions. This was
possibly because steric hindrance inhibited the
insertion of Ln-pyridine into the C=C bond (Table 2,
entry 23). Finally, the precursor for seven-membered
pyridine-fused cycle 1y was tried as a substrate but the
[a]
Reaction conditions: 1 (0.5 mmol), Y[N(TMS)2]3 (10
mol%), toluene (3 mL), sealed Schlenk tube equipped with
3
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10.1002/adsc.201901473
Advanced Synthesis & Catalysis
Schlenk tube equipped with a Teflon cap under N2,
100 °C, 24 h, isolated yield.
desired product was not obtained (Table 2, entry 24).
The sluggishness of this reaction likely resulted from
the poor steric orientation of the pyridine-Ln species
coordinated with remote ε C-C double bonds.
Replacing the nitrogen atom in the linker with another
heteroatom such as oxygen did not provide the
corresponding C-H cyclization product (Table 2, entry
25). The structure of 2n was confirmed by X-ray
crystallographic analysis.[19]
We next set out to investigate vinyl-substituted
quinoline-3-amines. Compared with the pyridine
analogues, these substrates showed better catalytic
efficiency. Both N-alkyl- and N-aryl-substituted
quinoline-3-amines were efficient substrates,
affording the corresponding products 2za–2zj in 79%–
98% yield (Table 3, entries 1–10). The structure of 2zf
was confirmed by X-ray crystallographic analysis.[19]
Further demonstrating the synthetic practicality of
this bicyclization process, the treatment of diverse
symmetrical or asymmetrical 3,5-diaminoalkenyl
functionalities attached to pyridine substrates were
next investigated, giving the double-insertion products
2zk–2zm as a 1:1 mixture of diastereomers in 72%–
78% yield. The structure of 2zk was confirmed by X-
ray crystallographic analysis.[19]
To gain some insight into the mechanism of this
rare-earth-metal-catalyzed
C-H
bond
activation/cyclization process, a set of control
experiments were conducted. First, 1H NMR
monitoring revealed that the addition of Y[N(TMS)2]3
(10 mol%) to 1a in toluene-d8 at 100 °C led to the
complete liberation of the (Me3Si)2N ligand (a new
peak at 0.08 ppm) from the catalyst[17a] and 1a was
cleanly converted into 2a (Figure 2).
To determine whether C-H activation is the rate-
determining step, a kinetic isotope effect (KIE) was
measured using parallel experiments. The initial rate
of cyclization of the deuterated N-allyl-N-
methylquinolin-3-amine (1za-d) was determined. Less
than 5% of the deuterated C-H cyclization product
2za-d was detected (Scheme 2a). The high KIE value
of 19 observed for the reaction between 1za/1za-d is
consistent with a turnover-limiting C-H activation step
(Scheme 2b). The yield of deuterated 2za-d obviously
increased when 20 mol% of Y[N(TMS)2]3 was used as
the catalyst (Scheme 2c). These results provided
evidence that C-H activation is the rate-determining
step in the catalytic cycle.
To further investigate the electronic preference of
the reaction, competitive cyclization of 1b and 1d with
different electronic characters was performed. The C-
H cyclization was favored by the more electron-rich
substrate 1b (Scheme 2d). To obtain further
information about the mechanism of the reactions
involving Bn2NH, a series of control experiments were
carried out. The catalytic performance of this in situ
mixture prompted us to isolate triaminoyttrium
complex Y-1 according to a reported procedure[18c]
(Scheme 2e). The catalytic activity of Y-1 was found
to be higher than that observed for Y[N(TMS)2] in
some cases (Scheme 2f and g). These results showed
that the HNBn2 additive possibly induced the
generation of activated triaminoyttrium species Y-1,
which underwent the C-H cyclization reaction.
Table 4. Bicyclization of vinyl-substituted pyridine-3-
amines.[a]
Reaction conditions: 1 (0.5 mmol), Y[N(TMS)2]3 (20
mol%), toluene (3 mL), Bn2NH (20 mol%), sealed
4
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10.1002/adsc.201901473
Advanced Synthesis & Catalysis
Figure 2. 1H NMR spectra monitoring the progress of the model reaction.
A plausible mechanism for the rare-earth-metal-
catalyzed C-H cyclization reaction is shown in Scheme
3. Initial deprotonation of HNBn2 by Ln[N(TMS)2]3
provides lanthanide amide I. Activation of the vinyl-
substituted pyridin-3-amine leads to the formation of
lanthanide-pyridine complex II with the liberation of
HN(SiMe3)2 or HNBn2. Coordination and sequential
insertion of C=C into the Ln-pyridine bond of II gives
intermediate III, which could undergo intermolecular
protonation with 1 to afford product 2 and regenerate
lanthanide species II.
Conclusion
We developed a new approach to synthesize 4-
azaindolines through the rare-earth-metal-catalyzed C-
H
bond
activation/cyclization
reaction
of
functionalized pyridine. In addition, the protocol was
successfully applied to the synthesis of naphthyridine
derivatives. This rare-earth-metal-catalyzed process
represents an important supplement toward late-
transition-metal-catalyzed approach to obtain 4-
azaindolines with 100% atom efficiency under mild
reaction conditions. Further studies on lanthanide-
catalyzed tandem insertion/cyclization reactions to
construct other useful N-heterocycles are underway in
our laboratory.
Scheme 2. Mechanistic Studies.
Experimental Section
General Procedure for the Synthesis of 4-Azaindolines
In a glove box, Y[N(SiMe3)2]3 (28.5 mg, 0.05 mmol, 10
mol%) was added to a Schlenk tube equipped with a
magnetic stirring bar and Teflon cap. Then, a mixture of
functionalized pyridine derivative (0.50 mmol) and amine
(0.05 mmol, 10 mol%) in toluene (3 mL) were added. The
sealed tube was taken out from the glove box and then
stirred at 100 °C for 24 h. After completion of the reaction,
the crude product was purified by flash column
chromatography on silica gel with ethyl acetate/hexane as
the eluent.
Acknowledgements
We thank the National Natural Science Foundation of China (No.
21572162), Natural Science Foundation of Zhejiang Province (No.
LQ18B020006), Foundation of Wenzhou Basic Scientific Research
Project (No. G20190009), Zhejiang Educational Committee of
China (Y201737383), Xinmiao Foundation of Zhejiang Province
(No. 2018R429056), and Wenzhou University for financial support.
Scheme 3. Proposed Mechanism.
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10.1002/adsc.201901473
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
FULL PAPER
Rare-Earth-Metal-Catalyzed
Synthesis
of
Azaindolines and Naphthyridines via C-H
Cyclization of Functionalized Pyridines
Adv. Synth. Catal. Year, Volume, Page – Page
Pengqing Ye, Yinlin Shao*, Fangjun Zhang*,
Jinxuan Zou, Xuanzeng Ye, and Jiuxi Chen*
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