Selective reductive cross-coupling of N-heteroarenes by an unsymmetrical PNP-ligated manganese catalyst

Article abstract of DOI:10.1016/j.jcat.2020.09.036

Reductive functionalization of N-heteroarenes remains to date a challenge due to the easy occurrence of direct reduction of such substances into non-coupling saturated cyclic amines. Herein, by developing an unprecedented manganese catalyst ligating with an unsymmetrical 2-aminotetrahydronaphthyridyl PNP-ligand, we have achieved a new reductive cross-coupling of indoles/pyrroles and N-heteroarenes. Mechanistic investigations show that the catalyst-enabled in situ capture of the partially reduced intermediates by interruption of the second transfer hydrogenation of N-heteroarenes constitutes the key to success for the present reaction. The developed chemistry proceeds with good substrate and functional group compatibility, high step and atom efficiency, excellent chemo and regioselectivity, and applicable for late-stage modification of pyridine-containing biomedical molecules, which has established a new platform allowing the linkage of aromatic systems into functional frameworks, and further development of unsymmetrical PNP organometallic complexes and related catalytic transformations.

Full text of DOI:10.1016/j.jcat.2020.09.036

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Selective reductive cross-coupling of N-heteroarenes by an unsymmetrical
PNP-ligated manganese catalyst
Zhenda Tan, Biao Xiong, Jian Yang, Chenggang Ci, Huanfeng Jiang, Min
Zhang
PII:
S0021-9517(20)30404-8
https://doi.org/10.1016/j.jcat.2020.09.036
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28 September 2020
Please cite this article as: Z. Tan, B. Xiong, J. Yang, C. Ci, H. Jiang, M. Zhang, Selective reductive cross-
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doi: https://doi.org/10.1016/j.jcat.2020.09.036
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Selective reductive cross-coupling of N-heteroarenes by an unsymmet
rical PNP-ligated manganese catalyst
Zhenda Tan a, Biao Xiong c, Jian Yang a, Chenggang Ci b,*, Huanfeng Jiang a, Min Zhang a,*
aKey Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510641, People’s Republic of China
bKey Laboratory of Computational Catalytic Chemistry of Guizhou Province, Department of Chemistry and Chemical
Engineering, Qiannan Normal University for Nationalities, Duyun 558000, P. R. China
cSchool of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China
ABSTRACT: Reductive functionalization of N-heteroarenes remains to date a challenge due to the easy occurrence of
direct reduction of such substances into non-coupling saturated cyclic amines. Herein, by developing an unprecedented
manganese catalyst ligating with an unsymmetrical 2-aminotetrahydronaphthyridyl PNP-ligand, we have achieved a
new reductive cross-coupling of indoles/pyrroles and N-heteroarenes. Mechanistic investigations show that the
catalyst-enabled in situ capture of the partially reduced intermediates by interruption of the second transfer
hydrogenation of N-heteroarenes constitutes the key to success for the present reaction. The developed chemistry
proceeds with good substrate and functional group compatibility, high step and atom efficiency, excellent chemo and
regioselectivity, and applicable for late-stage modification of pyridine-containing biomedical molecules, which has
established a new platform allowing the linkage of aromatic systems into functional frameworks, and further
development of unsymmetrical PNP organometallic complexes and related catalytic transformations.
Keywords: manganese catalysis, PNP ligand, hydrogen transfer, reductive cross-coupling, pyridyl ring
1. Introduction
Over the past decades, organometallic catalysis has greatly facilitated the advances of organic synthesis [1]. However, the
success is mainly based on the utilization of noble metals (e.g. Pd, Ru, Rh, and Ir) [2], and the high price associated with the limited
availability of noble metals generally constitutes the main cost of many processes in chemical production, which greatly limits their
practical applications. In this context, the replacement of noble metal catalysts with earth-abundant metallic ones for the production
of functional chemicals is of particular importance in sustainable chemistry, as it contributes to the conservation of finite precious
metal resources [3]. Among various base metals, manganese constitutes the third most abundant one in the Earth’s crust. Since
2016, the groups of Kirchner [4], Beller [5], Milstein [6], Kempe [7], and Liu [8] discovered that the Mn(I) pincer complexes
bearing strong bound PNP ligands were able to serve as efficient catalysts for dehydrogenation reactions, sometimes in conjunction
with hydrogen auto-transfer processes [9]. Interestingly, these catalysts, featuring long-term stability and high robustness toward
harsh conditions, can compete or even surpass the catalytic performance of some noble metal catalysts. Nevertheless, it is important
to note that most of these utilized PNP ligands are symmetrical. As such, the development of unsymmetrical PNP-ligated
Mn-catalysts remains an attractive subject to be explored, as it would offer the potential to result in new reactivity and selectivity in
catalytic transformations.
[M]
Ar
Ar
Ar
Ar
Ar
HN
+
HD
N
N
H
N
H
N
H
1
2
2-4
(X = CH or N)
3
[M]
HD
[MH2]
2nd TH
1nd TH
[MH2]
Ar
Ar
HN
Ar
2-1
Ar
2-2
Ar
2-3
1
N
N
N
N
H
H
3-1
Scheme 1. Envisioned reductive coupling reaction.
Partially or fully saturated N-heterocycles (e.g., piperidines, tetrahydropyridines, tetrahydroquinolines, and
tetrahydronaphthyridines) are extensively distributed in functional products (i.e., natural alkaloids, bioactive molecules,

pharmaceuticals, organo-catalysts, and functional materials) [10], and applied as versatile building blocks for various synthetic
purposes [11]. Consequently, the search for new approaches enabling efficient access to such N-heterocycles is of important
significance in scientific community. To date, although the reduction of N-heteroarenes offers a general way to realize the synthetic
purpose [12], the molecular diversity is easily restricted. Inspired by the stepwise catalytic hydrogenation of N-heteroarenes, we
believed that, by interruption of the hydrogenation process, the utilization of partially reduced intermediates as the coupling
partners for the next step of a given sequence would be a promising subject, as it paves new avenues to directly and diversely
access functionalized N-heterocycles that need multi-step synthetic procedures with the conventional approaches.
As our sustained effort toward the functionalization of N-heterocycles [13], we have recently reported an oxidative
-functionalization of tetrahydroquinolines [13d]. However, such a synthesis suffers from the drawbacks of the need for
pre-preparation of tetrahydroquinolyl reactants via hydrogenation of quinolines [12] or the cycloaddition of aryl nitriles with
alkenes [14], and the use of noble metal catalyst and less environ-mentally benign oxidants. From the viewpoint of step and atom
economy concerns, direct reductive linkage of two N-heteroarenes would be far more appealing. Therefore, we propose a new
synthetic protocol for the synthesis of -functionalized N-heterocycles by a strategy of reductive dearomatization of N-heteroarenes
followed by in situ capture of the hydrogenated intermediates. As illustrated in Scheme 1, the presence of a suitable catalyst ([M])
and hydrogen donor (HD) initially leads to the first transfer hydrogenation (1st TH) of N-heteroarene 2 and forms allylic amine 2-1
and its tautomers (2-2 and 2-3) [15]. Then, the desired product 3 is afforded via the nucleophilic addition of indoles/pyrrole 1 to
imine 2-3 followed by a tautomerization of the coupling adduct 3-1.
2. Experimental
2.1. Synthesis of PNP ligands and Mn-complexes
R1
R1
R1
[M], L
PR2Cl
N
N
NH
N
N
NH
N
N
NH2
R2P
[M] PR2
Ln
H
PR2
PR2
Br
Ph
H
CO
Ph
H
N
N
PPh2
PCy2
N
N
Mn
Mn
CO
CO
Br
N
N
P
P
Ph2
Cy2
CO
Mn-II
CO
Mn-I
Ph
H
N
Br
p-tol
H
N
PPh2
Br
PPh2
N
N
N
Mn
Mn
CO
N
Br
P
P
Ph2
Ph2
CO
Mn-III
Mn-IV
CO
H
N
PPh2
N
Mn
CO
Br
HN
P
Ph2
CO
Mn-V
Scheme 2. Preparation of unsymmetrical PNP Mn-complexes.
To achieve a selective synthesis of product 3, there should be a compatible system to ensure that the coupling between
nucleophile 1 and intermediate 2-3 by interruption of the second transfer hydrogenation (2nd TH) of the N-heteroarenes (from 2-3
to 2-4) is efficient as possible, thus suppressing the formation undesired byproduct 2-4. Enlightened by the relatively low
hydrogenation reactivity of PNP-Mn catalysts [4-8, 16], we believe that the development of a suitable PNP-ligated manganese
catalyst would offer a solution to resolve the key issue of chemo-selectivity. Attracted by the unique structures of our recently
reported tetrahydronaphthyridines (THNDs), [17] we whished to utilize THNDs to develop novel unsymmetrical PNP ligands, and
the relevant manganese catalysts with tunable three-dimensional structures and electron distribution. As shown in Scheme 2, we
successfully prepared five unsymmetrical PNP pincer manganese complexes (Mn-I−Mn-V) via the introduction of phosphine
groups onto both N-atoms of the THNDs followed by the coordination of manganese precursors (Mn(CO)5Br and MnBr2) with the
initially obtained PNP ligands (L1−L3, Scheme S1 in supporting information (SI)).
3. Practical applicability of the catalyst
3.1. Reaction condition optimization
With the availability of the manganese complexes, we then evaluated their catalytic performance toward the reductive
cross-coupling of 5-methoxy-1H-indole 1a and 2-phenyl-1,8-naphthyridine 2a with the use of i-propanol as the hydrogen supplier.
First, the reaction was per-formed at 130 oC for 20 h by using abundantly available i-propanol as the hydrogen donor (HD). Among
5 complexes tested (Table 1, entries 1−5), Mn-II exhibited the best activity and delivered product 3aa in 85% yield along with

trace of tetrahydronaphthyridine 2a-4. Noteworthy, the use of catalyst precursors Mn(CO)5Br or MnBr2, and either the absence of
Mn species or base failed to yield any desired product (entries 6−9), showing that both the PNP-ligated Mn-complex and base play
crucial roles on the product formation. Further, we screened different bases, hydrogen donors (HDs), solvents, temperatures, and
catalysts (entries 9−22, Table S2 in SI), but all of them were inferior to the conditions illustrated in entry 2. Thus, the optimal
reaction conditions (standard conditions) are as described in entry 2 of Table 1.
Table 1 Screening of Optimal Reaction Conditionsa.
MeO
[Mn], HD
MeO
+
additive
Ph
solvent
N
N
N
N
Ph
N
Ph
N
N
H
H
H
1a
3aa
2a
2a-4
HN
Entry
Catalyst
Mn-I
Mn-II
Mn-III
Mn-IV
Mn-V
Mn(CO)5Br
MnBr2
-
yield of 3aa/2a-4 (%)b
1
2
3
4
5
6
7
8
9c
28/5
85/2
35/0
2/0
32/15
-
-
-
-
Mn-II
a The mixture of 1a (0.2 mmol), 2a (0.25 mmol), cat. (2 mol %), t-BuONa (50 mol %), and i-PrOH (1.0 mmol) in t-amyl alcohol (1.5 mL)
was stirred at 130 oC for 20 h under N2 protection.
b NMR yield using nitromethane as an internal standard.
c Without base.
3.2. Substrate scope evaluation
Having the established the optimal reaction conditions, we then examined the substrate scope of the reductive cross-coupling of
two N-heteroarenes. First, various substituted indoles (1a−1i, for their structures see Scheme S2 in SI) in combination with
2-phenyl-1,8-naphthyridine 2a were tested. Gratifyingly, all the reactions proceeded smoothly and furnished the desired products in
moderate to excellent yields upon isolation (Scheme 3, 3aa−3ia). The electronic properties of the substituents on the indoyl
skeleton affected the product yields to some extent. Especially, indoles bearing electron-donating groups (3aa, 3ba, 3da, 3fa−3ha)
afforded the products in higher yields than that of indole with an electron-withdrawing group (3ia), suggesting that the reaction
involves a nucleophilic coupling (addition) step, which is in good agreement with the proposed pathway shown in Scheme 1.
Interestingly, 2-methyl-1H-pyrrolo[2,3-b]pyridine 1j, an indole analogue, effectively reacted with substrate 2a to deliver product
3ja in moderate yield. In addition to indoles, pyrrole derivatives (1k and 1l) also underwent efficient reductive cross-coupling with
2a, affording the desired products (3ka and 3la) in reasonable yields.
Mn-II
(2 mol %)
t-BuONa (50 mol %)
Ar
N
N
Ph
3
, isolated yield
R
R
i-PrOH (5 eq), t-AmOH
N
N
Ph
N
H
H
130 oC, 20 h, N2
HN
2a
1
MeO
N
N
Ph
Ph
N
N
Ph
N
N
Ph
H
H
H
HN
HN
3aa
HN
3ca, 45%
, 78%
3ba
, 65%
H2N
N
H
N
Ph
N
H
N
Ph
N
H
3fa
N
HN
HN
HN
, 62%
3da
3ea
, 84%
, 55%
MeO
Br
N
H
N
Ph
N
N
Ph
Ph
N
H
3ia
N
Ph
H
HN
HN
HN
HN
3ha
3ga
, 78%
, 83%
, 60%
N
N
N
N
H
N
Ph
N
N
Ph
H
H
HN
HN
3ja
3ka
, 41%
, 48%
3la
, 66%
Scheme 3. Variation of Indoles and Pyrroles.
Subsequently, we turned our attention to the variation of both coupling partners (see Scheme S2 and S3 in SI for their structures).
As illustrated in Scheme 4, all the indoles selectively coupled with the -site of the sterically less-hindered pyridyl ring in
1,8-naphthyridines (2b−2l), affording the desired products in moderate to high isolated yields. Although 1,8-naphthyridine 2b has

two reactive -sites, indoles 1a and 1i only reacted with one site and generated the mono-coupling products (3ab, 3ib). The
retention of one -site would offer the potential for further molecular complexity [11]. Gratifyingly, 2-heteroaryl-1,8-naphthyridine
2l also underwent efficient cross-coupling to give the 2-thiophenyl THND 3hl, and the obtained product has the potential to be
applied as hemilabile ligand in coordination chemistry and catalysis [18]. In addition to the 2-(hetero)aryl-1,8-naphthyridines, other
types of N-heteroarenes, such as pyridine-fused pyrazines (2m−2p) and pyrimidine (2q), were also amenable to the transformation,
affording the desired products in good yields (3em, 3an, 3ao, 3ap and 3fq). Noteworthy, in such bicyclic N-heteroaromatic systems
(2m−2q), the cross-coupling selectively occurs on the pyridyl ring. Such a phenomenon is rationalized as follows: except for the
factor of less steric hinderance, the less-electrophilic pyridyl ring has stronger binding capability with the Mn-catalyst, which
preferentially directs the reduction on the pyridyl ring and forms the requisite active intermediates.
X
R1
R1
(2 mol %)
X
Mn-II
t-BuONa (50 mol %)
R2
R2
N
N
N
N
i-PrOH (5 eq), t-AmOH
H
N
130 oC, 20 h, N2
H
2
HN
1
(X = CH or N)
3
, isolated yield
MeO
R'
N
H
N
R
N
N
R
H
HN
HN
3ff
3fg
3fh
3ab
3ac
3ad
3ae
(R = 4-NO2C6H4; R' = H), 60%
(R = 4-BrC6H4; R' = H), 68%
(R = Ph; R' = Me), 55%
(R = H), 65%
(R = 4-CF3C6H4), 85%
(R = 4-ClC6H4), 81%
(R = Naphth), 65%
Br
F
N
N
R
N
N
H
H
HN
3ib
3id
HN
3mi
, 40%
OMe
,
(R = H) 48%
(R = 4-ClC6H4), 71%
MeO
MeO
N
N
N
N
H
3ak
N
H
3aj
, 63%
HN
HN
, 58%
N
S
N
N
N
H
3em
N
H
HN
MeO
HN
3hl
, 62%
N
, 62%
MeO
N
N
H
N
N
H
3an
N
HN
3ao
, 78%
HN
, 72%
MeO
N
N
N
H
N
Ph
N
N
H
HN
3fq
, 68%
HN
3ap
, 52%
Scheme 4. Variation of Both N-heteroarenes.
R1
R2
R2
R2
Mn-II
(2 mol %)
t-BuONa (50 mol %)
N
N
N
i-PrOH (5 eq), toluene
+
Br
Br
1a 1b
indole
,
Bn
Bn
HN
Ph
Br
MeO
N
N
Bn
Bn
HN
HN
(R1 = Me; R2 = H), 51%
(R1 = OMe; R2 = Br), 42%
3bs
3ar
O
O
O
O
N
N
H
H
N
H
NH
H
O
MeO
Cl
Ph
O
3bu
, 38%
3bt
, 61%
from Estradiol benzoate
from Bornyl quinoline-6-carboxylate
Scheme 5. The catalytic transformation of quinoline derivatives.
However, the more challenging quinoline derivatives were not compatible with the transformation. To overcome the obstacle of
the reactivity, we found that, through a simple pre-treatment of quinolines with benzyl bromide, the in situ formed quinolinium salts
[19] could smoothly react with indoles to afford the reductive cross-coupling products in moderate yields (Scheme 5, 3ar and 3bs),
which offers an alternative way to access N-non-substituted -functionalized tetrahydro-quinolines via N-debenzylation of the
obtained products [20]. Interestingly, the synthetic protocol was also applicable for catalytic transformation of bornyl

quinoline-6-carboxylate (1t) and estradiol benzoate (1u), the key compositions used as analgesic and antioxidative and
antiproliferative agent respectively, and they smoothly reacted with indole 2b to afford the coupling products (3bt and 3bu) in
moderate yields. These examples demonstrate the potential of the developed chemistry in late-stage modification of
pyridine-containing biomedical molecules.
4. Mechanistic insights
To gain mechanistic insights into the reaction, several control experiments were conducted (Scheme 6). Interruption of the model
reaction after 5 h delivered product 3aa, tetrahydro-1,8-naphthyridine 2a-4 and dihydro-1,8-naphthyridine 2a-3 in 18%, 1% and 1%
yields, respectively (eq. 1). The treatment of indole 1a with 2a-4 under the optimal conditions failed to generate product 3aa (eq 2),
indicating that the reaction involving compound 2a-4 as the intermediate is less likely. In contrast, compound 2a-3 smoothly
coupled with indole 1a to afford 3aa in good yield (eq. 3), suggesting that the dihydronaphthyridine is the key reaction intermediate.
Moreover, the coupling of 2a and indole 1b in deuterated i-PrOH-d8 yielded product 3ba-dn with different deuterium ratios on
both pyridyl ring, showing that the hydrogen atoms from i-PrOH are transferred to 1,8-naphthyridine 2a, and intermediate
dihydro-1,8-naphthyridine involves tautomerization (see 2a-1, 2a-2 and 2a-3 in Scheme 1). All these results are in good
agreement with the reaction pathway proposed in Scheme 1.
Standard
conditions
5 h
1a
3aa
2a
, 18%
(1)
N
2a-3
N
, 1%
Ph
N
N
2a-4
Ph
, 1%
H
Standard conditions
20 h
1a
(2)
(3)
2a-4
1a
3aa
, 0%
Standard conditions
20 h
2a-3
3aa
, 82%
20% D
10% D
N
Mn-II
(2 mol %)
50% D
20% D
(4)
t-BuONa (0.5 eq)
i-PrOH-d8 (5 eq)
toluene
10% D
1b
2a
N
H
N
3ba-dn
H
Scheme 6. Control Experiments.
Further, DFT calculation was performed to explore the mechanism in detail. Fig. 1 shows the overall potential energy profile
computed for the reaction between 1a and 2a, in which all of the structures were optimized in isopropanol solution. The first step is
the formation of MnH (D) complex. From A, the mechanism proceeds first with the Mn−Br bond cleavage and gives the MnL+ (B)
and Br- without energy barrier. This is an easy step at room temperature (endothermic about 4.5 kcal mol-1). Next, the attack of
(CH3)2CHO- anion on the Mn atom of B forms C. Herein, C is 20.0 kcal mol-1 stable than complex A. To form the required active
specie, an energy barrier of 17.0 kcal mol-1 must be overcame, reaching the MnH (D) complex through a typical H-transfer
transition state, TSCD. Then, hydride transfer to the ortho-carbon of pyridyl ring proceeds through a transition state TSDE with
energy barriers of 15.5 kcal mol-1. Naturally, there can be double-bond-shift isomerization from E to E´ without energy barrier in an
exergonic step (ΔG = -2.6 kcal mol-1). Thus, the subsequent step is the proton transfer from i-PrOH to the meta-carbon of pyridyl
ring with a barrier of 10.0 kcal mol-1 and is endergonic, with ΔG = 9.7 kcal mol-1. Once intermediate F has formed, the released B
will react with i-PrO- to form C, that is, the regeneration of catalyst. Note that, in TSDE and TSE´F, MnH (D) complex as an
important active specie provides H- to 2a through hydride-transfer process, while the i-PrOH as proton donner gives the H+. The
last step is 2a-3 (F) reacts with 1a to form 3aa (G). This is an intramolecular H-transfer accompanied with C−C bond formation. As
could be expected that this will overcome a higher energy barrier. According to previous calculation results, the solvent and
complex B might be involved in this step [19a, 21]. The calculation results show that the energy barrier of TSFG is 20.0 kcal mol-1
under the assistant of i-PrOH (v.s. TSFG without i-PrOH, 55.8 kcal mol-1). Moreover, the thermodynamic was also favored by B
with an endothermic step (F coordinate with B) of 4 kcal mol-1, whereas B is released when 1a and i-PrOH start to attack F. This is
attributed to the high steric hinderance in Mn(I) center and weak Mn−N bond in F-B complex. Thus, B is not involved in formation
of 3aa from F to G.
5. Conclusions
In summary, by developing an unprecedented manganese catalyst (Mn-II) ligating with an unsymmetrical
2-aminotetrahydronaphthyridyl PNP ligand, we have achieved a new reductive cross-coupling reaction of indoles/pyrroles and
non-activated N-heteroarenes with the use of i-propanol as the hydrogen supplier. Mechanistic investigations indicate that the
catalyst-enabled in situ capture of the reduced intermediates by interruption of the second transfer hydrogenation of the
N-heteroarenes constitutes the key for the reaction. The catalytic transformation proceeds with high step and atom efficiency,
excellent regio and chemo-selectivity, good substrate and functional compatibility, and applicable for late-stage modification of
pyridine-containing biomedical molecules. The work presented offers a valuable platform allowing direct linkage of inert aromatic
systems into functional frameworks, and further development of other unsymmetrical PNP-ligated organometallic complexes and
related catalytic applications.

Fig. 1. Schematic representation of the potential energy surface for the formation of 3aa (G). (free energies in kcal mol-1)
Acknowledgements
We thank the National Key Research and Development Program of China (2016YFA0602900), National Natural Science
Foundation of China (21971071), the scientific and technological project for social development of Qiannan (Qiannankeheshezi
[2017]91), the Key Laboratory of Computational Catalytic Chemistry of Guizhou province (Qianjiaohe KYzi [2017]3), and
Youth Program of National Natural Science Foundation of China (No. 21801138) for financial support.
Appendix A. Supplementary material
Supplementary data to this article can be found in SI
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Declaration of Interest Statement
All the authors declare that we have no financial and personal relationship with people and organizations that can
inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any
product, service and/or company that could be construed as influencing the position presented in, or the review of, the
manuscript entitled.

Ar
Br
Ph
H
N
N
H
PPh2
Ar
N
Ar
HN
Mn
CO
N
CO
N
H
P
Ph2
Ar
Mn-II
N
High step and atom-efficiency
Unsymmetrical new PNP Mn catalyst


Direct N-heteroaromatic transformation
Excellent chemo and regio-selectivity 

By developing an unprecedented manganese catalyst ligating with an unsymmetrical 2-aminotetrahydronaphthyridyl
PNP-ligand, a new reductive cross-coupling of indoles/pyrroles and N-heteroarenes has been demonstrated.
Reductive highlights
Reductive functionalization of N-heteroarenes
Unsymmetrical PNP Mn catalyst
Direct linkage of two different N-heteroarenes
High step and atom efficiency
Excellent chemo and regioselectivity