Selective synthesis of nitrogen bi-heteroarenes by a hydrogen transfer-mediated direct α,β-coupling reaction

Article abstract of DOI:10.1039/c7ob01434a

By an external hydrogen transfer-mediated activation mode, we herein demonstrate a new palladium-catalyzed direct α,β-coupling of different types of N-heteroarenes. Such a selective coupling reaction proceeds with the advantages of operational simplicity,

Full text of DOI:10.1039/c7ob01434a

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Selective synthesis of nitrogen bi-heteroarenes by
a hydrogen transfer-mediated direct α,β-coupling
reaction†
Cite this: DOI: 10.1039/c7ob01434a
Received 13th June 2017,
Accepted 4th July 2017
Xiu-Wen Chen,a He Zhao,a Biao Xiong,a Huan-Feng Jiang, a Pierre. H. Dixneufb
DOI: 10.1039/c7ob01434a
a
and Min Zhang
*
rsc.li/obc
By an external hydrogen transfer-mediated activation mode, we serving as alternative hydrogen suppliers have also been ele-
herein demonstrate a new palladium-catalyzed direct α,β-coupling gantly utilized for the reduction of various unsaturated
of different types of N-heteroarenes. Such a selective coupling chemical bonds,7 hydrogen-borrowing reactions8 and transfer
reaction proceeds with the advantages of operational simplicity, hydrogenative coupling reactions.9 Despite these significant
high atom-economical efficiency, and use of safe and abundant achievements, the application of the TH strategy in the acti-
i-propanol as the activating agent, offering a practical way to vation of N-heteroarenes to generate bi-N-heteroaryl motifs,
access nitrogen bi-heteroarenes. Preliminary exploration has the core structures of numerous bioactive molecules, func-
revealed that the obtained bis-1,10-phenanthroline 2qq’ as
ligand is capable of improving a copper catalyst for C–C bond for- natural products,10 still remains an unexplored goal.
mation. The work reported in this paper has built an important Upon a thorough literature investigation, the early metallic
a
tional materials, dyes, agrochemicals, pharmaceuticals and
basis for the creation of extended π-conjugated systems that are of sodium-mediated α,β-coupling of quinolines was reported in
high significance in biological, medicinal, materials and synthetic 1980 by Carlier and Einhorn.11a Then, the Aksenov group
organic chemistry as well as catalysis.
observed that NaH also could be employed to achieve the same
reaction.11b Despite the utility of these two precedents, they
suffer from limited substrate scope, use of air- and moisture-
sensitive reagents (Na and NaH), the need for stringent protec-
tions, and harsh reaction temperatures (160–190 °C). Hence,
Introduction
Transfer hydrogenation (TH) constitutes a fundamental tool in there is a demand for new protocols that enable synthesis
organic chemistry, which has been considered as a promising diversity from stable raw materials and with easy manipulations.
alternative to conventional hydrogenation methods since it
Prompted by our recent efforts in the creation of function-
does not need special equipment such as autoclave and flam- alized N-heterocycles by a hydrogen transfer strategy,12 we
mable H2 gas. As a result, a series of hydrogen donors1–3 have wished herein to report a new palladium-catalysed synthesis of
been explored for various synthesis purposes. For example in nitrogen bi-heteroarenes (2) by a hydrogen transfer-mediated
recent years, Li and co-workers reported the synthesis of direct α,β-coupling of different types of N-heteroarenes (1), in
amine derivatives directly from phenol derivatives and amines which, the abundant and safe i-propanol was employed as the
(ammonia) by using HCO2Na as a TH reagent.4 In the presence activating agent (eqn (1)).
of Hantzsch esters, the Zhou group realized the enantio-
selective TH of various N-heteroarenes.5 Moreover, the
ð1Þ
Bruneau group successfully developed the non-directed
C(sp3)–H bond alkylation by using HCO2H as the hydrogen
source.6 More recently, the abundant and sustainable alcohols
aKey Lab of Functional Molecular Engineering of Guangdong Province, School of
Results and discussion
Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510641, China. E-mail: minzhang@scut.edu.cn
To test the feasibility of the above idea, the reaction of
2-phenyl-1,8-naphthyridine (1a) in toluene was performed at
125 °C by using NaOH as a base and i-propanol as the external
bCentre of Catalysis and Green Chemistry-OMC, Institut Sciences Chimiques de
Rennes UMR 6226-CNRS-Universite de Rennes 1, Campus de Beaulieu,
35042 Rennes, France
hydrogen donor (HD). Among four catalysts tested (Table 1,
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7ob01434a
entries 1–4), both Pd catalysts were able to afford the
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Table 1 Screening of optimal reaction conditionsa
Entry Catalyst
HD
Solvent
2aa′ Yieldb/%
1
2
3
4
5
6
7
8
[RuCl2(p-cymene)]2 i-Propanol
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Trace
Trace
50
42
[Cp*IrCl2]2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaH (2.7%)
Pd(OAc)2
Pd(OAc)2
i-Propanol
i-Propanol
i-Propanol
—
i-Propanol
i-Propanol
i-Propanol
i-Propanol
i-Propanol
i-Propanol
Methanol
Ethanol
—
—
(—, <5, 31)c
9
<5
9
DMSO
10
11
12
13
14
15
16
17
18
1,4-Dioxane 63
1,4-Dioxane (57, 61)d
1,4-Dioxane 20
1,4-Dioxane 22
1,4-Dioxane <5
HCO2Na
(Me2Si2H) 2O 1,4-Dioxane
9
—
—
1,4-Dioxane
i-Propanol
i-Propanol
1,4-Dioxane 55e
1,4-Dioxane Tracef
a Reaction conditions: Unless otherwise stated, all reactions were
carried out by using 1a (0.2 mmol), HD (0.6 mmol), catalyst (3 mol%),
NaOH (0.2 mmol), and solvent (1.0 mL) at 125 °C for 16 h under a
N2 atmosphere. b Yield of isolation. c Yields are listed with respect to
using Na2CO3, MeONa and t-BuOK as the bases, respectively. d Yields
are listed with respect to the temperatures 120 °C and 140 °C, respect-
ively. e i-propanol: 0.4 mmol. f i-propanol: 3 mol% or 10 mol%.
Scheme 1 The
α,β-coupling
of
1,8-naphthyridyl
derivatives.
Conditions: 1 (0.2 mmol), Pd(OAc)2 (3 mol%), NaOH (0.2 mmol), i-pro-
panol (0.6 mmol), 125 °C.
on the aryl ring of the reactants (1) have little influence on the
product formation. Gratifyingly, the less reactive non-substi-
tuted 1,8-naphthyridine (1g) and 2-alkyl-1,8-naphthyridine (1h)
were also applicable for the transformation to give the products
(2gg′, 2hh′) in reasonable yields. Similarly, the alkyl and aryl di-
substituted 1,8-naphthyridines (1i–1l) underwent effective
α,β-coupling to generate the tetra-substituted products (2ii′–2ll′).
In comparison, the diaryl-substituted 1,8-naphthyridines were
able to afford the corresponding products (2ee′, 2ff′) in much
higher yields than those arising from the coupling of mono-aryl-
or non-aryl-substituted 1,8-naphthyridines (2aa′–2dd′, 2gg′–2ll′),
which might be ascribed to the fact that diaryl-substituted sub-
strates have low-LUMO regarding the ease of transfer hydrogen-
ation. It is noteworthy that, performing the reaction of two
different 1,8-naphthyridines (1a, 1g) led to two homo-coupling
(2aa′, 2gg′) and two cross-coupling (2ag′, 2ga′) products in
similar yields (eqn (2)), supporting the fact that the reaction
intermediates possess the reactive α- and β-sites. However, the
reactions of 2- and 3-substituted 1,8-naphthyridines were
unable to give the corresponding products, presumably because
of the influence of steric hindrance.
α,β-coupling product 2aa′ in 50% and 42% yields along with a
small portion of tetrahydro-1,8-naphthyridine 1a′ (<15%),
respectively. However, the absence of i-propanol or Pd catalyst
failed to yield any desired product (entries 5 and 6), showing
that both are essential for product formation. Then, several
conventional bases (entry 7) and solvents (entries 8–10) were
tested by using Pd(OAc)2 as the catalyst. 1,4-Dioxane appeared
to be a better choice and gave 2aa′ in 63% yield (entry 10).
However, the change of the reaction temperature was not fruit-
ful since no increase in yields was found (entry 11).
Furthermore, several hydrogen donors were screened (entries
12–15), but they proved to be less effective as compared to
i-propanol. Finally, using the same loading of the NaH catalyst
as reported by the Aksenov group11b led to no product for-
mation in our reaction system (entry 16), decreasing the
amount of i-propanol diminished the product yield (entry 17),
and the presence of a catalytic amount of i-propanol (3 mol%
or 10 mol%) gave only a trace of product 2aa′, suggesting that
the metal hydride species is unable to regenerate. Thus, the
optimal conditions are as described in entry 10 of Table 1.
With the optimal reaction conditions established, we then
examined the generality and the limitation of the synthesis pro-
tocol. First, different 2-aryl(heteroaryl)- and 2,3-diaryl-1,8-
naphthyridines were employed for the transformation. As illus-
trated in Scheme 1, all the reactions proceeded smoothly to
furnish the α,β-coupling products in reasonable to good isolated
yields (2aa′–2ff′), and the electron properties of the substituents
ð2Þ
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Scheme 4 Plausible pathway of the α,β-coupling of N-heteroarenes.
Scheme 2 The α,β-coupling of different N-heteroarenes.
cally less-hindered pyridyl ring. Then, the model reaction was
interrupted after 5 h to observe the reaction intermediates.
By means of GC-MS analyses, product 2aa′, tetrahedron
naphthyridine 1a′, enamine (1a-B) or imine (1a-C) were
detected in 9%, 2% and 1% yields, respectively (eqn (4), and
ESI Scheme S3†). Furthermore, the treatment of the mixture of
1a-B and 1a-C in 1,4-dioxane gave product 2aa′ in 76% yield
(eqn (5)), suggesting that the coupling of these two intermedi-
ates and the formation of product 2aa′ do not need a catalyst.
The reaction of 1a′ under standard conditions failed to afford
2aa′ (eqn (6)). These results clearly indicate that 1a-B and 1a-C
are the key reaction intermediates, and the conversion of tetra-
hedron naphthyridine 1a′ into product 2aa′ is difficult, which
rationalizes the product yields being somewhat low in some
cases (see Schemes 1 and 2).
Based on the above observations, a plausible reaction
pathway is depicted in Scheme 4. The N-heteroarene 1 is
initially activated by the hydrogen transfer of [MH2] arising
from the metal catalyst and hydrogen donor (i-propanol),
affording allylic amine A and its tautomer enamine B, and
imine C. Then, the β-site of B would be able to undergo
nucleophilic addition to the α-carbon of C, thereby releasing
the coupling adduct D. Finally, the auto-dehydroaromatization
of D would give rise to product 2.
Subsequently, we turned our attention to the application of
other N-heteroarenes. First, the more challenging quinoline
derivatives were tested. As shown in Scheme 2, all the sub-
strates were amenable to the synthesis protocol, furnishing the
2,3-biquinolines (2mm′–2oo′) in acceptable yields. 2,3-
Diphenylpyrido[2,3-b]pyrazine (1p), a representative polynitro-
gen heteroarene, was successfully converted into the desired
product 2pp′ in 48% yield. Interestingly, the catalytic system
was also compatible with the transformation of 1,10-phenan-
throline (1q), affording the new bis-1,10-phenanthroline 2qq′
in 32% yield, which has the potential to be applied as a tetra-
dentate ligand in organometallic chemistry and catalysis as
1,10-phenanthroline–metal catalysts were shown to be
crucial.13
To gain insight into the reaction information, we performed
several verification experiments (Scheme 3). The coupling of 1c
was surveyed by employing deuterium-labeled i-propanol as
the activating agent (eqn (3)). The H-NMR analysis showed no
H/D exchange on the m-tolyl unit, whereas different H/D ratios
was observed on the naphthyridyl skeleton (2cc′-dn), which
shows that the reaction undergoes
a hydrogen transfer
Finally, we were interested in demonstrating the application
of the obtained compounds. In consideration of the extensive
pathway, rather than a nitrogen atom-directed otho-C–H bond
activation. And the coupling occurred selectively at the steri-
applications of 1,10-phenanthroline (L1) as
a ligand in
Scheme 3 Verification experiments.
Fig. 1 Comparison of the catalytic performance of L1 and L2 (2qq’).
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catalysis, both L1 and the new product 2qq′ (L2) were
employed as the ligands for the copper-catalysed α-arylation of
deoxybenzoin 4a with 1-iodo-4-methoxybenzene 3a.13d As
shown in Fig. 1, by using 10 mol% of CuI, 5 mol% of L2
exhibited a much better catalytic performance than that of
10 mol% of L1, and the desired α-arylation product 5aa was
afforded in a higher yield within a shorter reaction time while
using L2 as the ligand.
H. Y. Zeng, S. A. Girard, F. Wang, N. Chen and C. J. Li,
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Conclusions
In summary, by an external hydrogen transfer-mediated acti-
vation mode, we herein demonstrate a new palladium-cata-
lyzed direct α,β-coupling of different types of N-heteroarenes.
Such a homo-coupling reaction proceeds with the advantages
of operational simplicity, high atom-economical efficiency,
and the use of safe and abundant i-propanol as the activating
agent, offering a practical way to access bi-N-heteroarenes.
Preliminary exploration has revealed that the obtained bis-
1,10-phenanthroline 2qq′ as a ligand is capable of improving
the copper catalyst for C–C bond formation. The work reported
in this paper has built an important basis for the creation of
extended π-conjugated systems that are of high significance in
biological, medicinal, materials and synthetic organic chem-
istry as well as catalysis.
8 Selected examples on hydrogen-borrowing reactions:
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Acknowledgements
We thank the Science and Technology Program of GuangZhou
(201607010306), the National Natural Science Foundation of
China (21472052), the Fundamental Research Funds for the
Central Universities (2017ZD060), “1000-Youth Talents Plan”,
and Science Foundation for Distinguished Young Scholars of
Guangdong Province (2014A030306018) for their financial
support.
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