Catalytic Conversion of N-Heteroaromatics to Functionalized Arylamines by Merging Hydrogen Transfer and Selective Coupling

Article abstract of DOI:10.1021/acscatal.0c00394

To date, although tremendous advances have been made in N-heteroaryl C-H functionalization, there remain significant unmet challenges in the deconstruction of extensively applied but poorly reactive N-heteroaromatics to useful frameworks. Here, by a strat

Full text of DOI:10.1021/acscatal.0c00394

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Article
Catalytic Conversion of N-Heteroaromatics to Functionalized
Arylamines by Merging Hydrogen Transfer and Selective Coupling
Zhenda Tan, Cheng-gang Ci, Jian Yang, Yang Wu, Liang Cao, Huanfeng Jiang, and Min Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00394 • Publication Date (Web): 09 Mar 2020
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Catalytic Conversion of N-Heteroaromatics to Functionalized
Arylamines by Merging Hydrogen Transfer and Selective Coupling
Zhenda Tan,a Chenggang Ci,b Jian Yang,a Yang Wu,a Liang Cao,a Huanfeng Jianga and Min Zhanga,*
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aKey Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510641, 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.
ABSTRACT: To date, although tremendous advances have been made on N-heteroaryl C−H functionalization, there remain
significant unmet challenges in deconstruction of extensively applied but poorly reactive N-heteroaromatics to useful frameworks.
Here, by a strategy merging hydrogen transfer and selective coupling, we present a ruthenium-catalyzed deconstruction of N-
heteroaromatics to functionalized arylamines with 2-aminoaryl methanols. The reaction is achieved via sequential functionalization
of the β and -sites of the initially formed N-heteroarenium salts followed by a C−N cleavage, proceeding with the striking features
of broad substrate scope, excellent functional groups tolerance, high chemo-selectivity and atom-efficiency, and applicable for
streamline synthesis of some biomedical molecules. The strategy utilized will pave the avenues for further development of catalytic
transformations of inert organo-systems to functional frameworks.
KEYWORDS: N-heteroaromatics, hydrogen transfer, selective coupling, ruthenium catalysis, pyridyl ring, arylamines
N-Heteroaromatics are ubiquitous in natural compounds,
bioactive molecules, pharmaceuticals, agrochemicals, ligands,
chemosensors, functional materials, etc.1-3 Among them,
pyridine ring is perhaps the most widely distributed core
structure. Consequently, the exploration of pyridyl ring-based
transformations is of important significance in scientific
community, as it not only enriches the connotation of N-
heteroaromatic reactivities, but also paves the ways to access
novel products with original biological, chemical and physical
properties. Over the past decades, significant advances have
been made on heteroaryl C−H functionalization, such as the
cross-coupling of preinstalled reagents with organo halides,
directing group-assisted site-selective coupling, and Minisci-
type of radical reaction.4-7 Interestingly, Sarpong et al. have
recently reported deconstructive functionalization of cyclic
amines, which opens new avenues to access valuable
products.8-9 However, due to the thermodynamic stability and
kinetic inertness, there remain significant unmet challenges in
catalytic deconstruction of N-heteroaromatics to functional
frameworks.
of 1,8-naphthyridines by using tetrahydroquinolines as inert
hydrogen Herein, we envisioned
donors.49
a
difunctionalization of N-heteroaromatics via transfer
hydrogenative dearomatization as a substrate-activating mode.
As shown in protocol 1 of Scheme 1, the first transfer
hydrogenation (1st TH) of N-heteroaromatic 1 generates
transient imine and enamine intermediates,49-50 which would
be able to trap bifunctional agent 4’ bearing both nucleophilic
and electrophilic sites, and produce ring-fused N-heterocycle
5-a. However, upon a thorough investigation of various
catalysts ([M]), hydrogen donors (HDs) and coupling agents,
we noticed that such a protocol was not feasible as the reaction
tended to fully reduce 1 to the over-hydrogenated byproduct
1’.51-52 So, to achieve the synthetic purpose, there should be a
compatible catalyst system to ensure that the coupling step by
interruption of the 1st TH of N-heteroaromatics should be
faster than the 2nd TH process.
Scheme 1. Strategy of difunctionalization of N-heteroarenes
(1) Initial idea
E
+E
[M],
+
HD
+
N
H
N
Nu
5-a
-Nu
N
H
1
, trace
1'
4'
, major product
In recent years, hydrogen auto transfer-mediated chemical
bond formation has emerged as an appealing tool in
(2) New merging strategy
E
(1)
R
2
Br
+
N
construction
of
various
valuable
products.10-15
N
Nu
5-c
4'
(2) [M], HD,
N
1
3-c
R
Advantageously, H2O is generally generated as the byproducts
in these transformations. For instance, the hydrogen borrowing
methodologies have been elegantly utilized for the alkylation
of active amines and carbo nucleophiles with alcohols. In this
regard, significant progress has been made by the groups of
Beller,16-19 Milstein,20-22 Kempe,23-27 Kirchner,28-30 and others31-
37. Krische has demonstrated outstanding contributions on
hydrogen-mediated C−C bond formations between unsaturated
hydrocarbons and alcohols.38-41 With the use of formic acid as
the hydrogen donor (HD), the Bruneau group has reported
non-directed C(sp3)−H alkylation of cyclic amines.42-45 Li and
Zeng have successfully converted phenol derivatives into
amines.46-48 Recently, we have reported an -functionalization
R
R
Br
less-favored
+E
cyclization
2
2nd TH
E
-Nu
[M], HD
4'
favored
+
-Nu
5-b
Br-
N
N
- HBr
N
3-b
N
1st TH
R
3-a
R
3
R
R
(3) New observation arising from initial attempt
[Cp*IrCl2]2 (1 mol%)
OH
NH2
+
t-BuOK (50 mol%)
NH
N
Br-
3aa
t-AmOH, 120 oC, 18 h
N
4a
Ph
5aaa
Ph
base
[M]
, 65% yield
[MH2]
+
O
C-N bond cleavage
N
N
H
N
NH2
4a'
3aa-b
Ph
Ph
5aaa-c
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[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
t-BuONa
t-BuONa
t-BuONa
80
Associating with the above information, we proposed a
strategy merging hydrogen transfer and selective coupling, and
the synthesis of ring-fused N-heterocycle 5-c is shown in
protocol 2 of Scheme 1. A simple pre-treatment of N-
heteroarene 1 with alkyl bromide 2 initially forms N-
heteroarenium salt 3.53-56 The 1st TH of salt 3 generates the N-
alkylated allylic amine 3-a and its tautomer enamine 3-b.
Here, it is important to note that, in comparison with the N-
non-substituted enamine, the 2nd TH of more electron-rich
enamine 3-b to byproduct 3-c would be less-favored, whereas
the -site of 3-b is beneficial to the coupling process and
formation of iminium 5-b via electrophilic coupling with agent
4’. Then, the intramolecular nucleophilic cyclization of 5-b
yields product 5-c.
1
2
3
4
5
6
7
8
(48, 63, 70)d
(80, 78, 58)e
aUnless otherwise stated, the reaction was performed with 3aa (0.25 mmol), 4a
(0.25 mmol), cat. (1 mol %), base (50 mol %) in toluene (1.5 mL) at 120 oC for
18 h under N2 protection. bNMR yield by using nitromethane as an internal
standard. ct-AmOH as the solvent. dYields are with respect to the use of DMF,
e
1,4-dioxane, t-AmOH as the solvents, respectively. Yields are with respect to
the temperature at 120 oC, 130 oC, 110 oC, respectively.
Scheme 2. Variation of Quinolines
9
HO
R2 Br
R1
R1
R1
2y
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11
12
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N
H2N
standard conditions
NH
R2
N
N
Br
R2
4a
5xya
3xy
1x
Br
The above idea prompted us to test the reaction of
quinolinium salt 3aa and 2-aminobenzyl alcohol 4a in the
presence of our previously employed [Cp*IrCl2]2/t-BuOK
system (protocol 3 in Scheme 1).49 In which, alcohol 4a was
employed as the hydrogen donor (HD), and its
dehydrogenated counterpart 4a’ was expected to serve as the
bifunctional agent. Interestingly, although the reaction did not
afford the anticipated product 5aaa-c, a synthetically useful
aniline 5aaa, via a C−N bond cleavage of 5aaa-c, was
obtained in 65% yield. Based on this finding, we wish herein
NH
N
NH
N
Ph
Ph
82%
5baa,
5aaa
, 78%
Br
F
Cl
NH
N
N
NH
N
NH
N
Ph
Ph
5eaa
, 85%
5caa
, 76%
5daa
5gaa
, 82%
Ph
O
MeO
5faa
MeO
NH
Ph
NH
, 60%
N
NH
N
5haa
, 62%
, 78%
Ph
to report
a catalytic conversion of non-activated N-
Ph
PhS
heteroaromatics to functionalized arylamines by a strategy
merging hydrogen transfer and selective coupling.
NH
N
NH
N
Ph
NH
N
5iaa
, 71%
To formulate a more efficient catalytic system, the synthesis
of product 5aaa from 3aa and 4a was chosen as a model
system to evaluate different reaction parameters (Table 1).
Gratifyingly, we found that the more cost-effective [Ru(p-
cymene)Cl2]2 exhibited even better efficiency than [IrCp*Cl2]2
(entries 1 in Table 1 and protocol 3 in Scheme 1). So, we then
focused on screening different ruthenium catalysts,57 and the
results showed that only [Ru(p-cymene)Cl2]2 exhibited the
best catalytic performance (entries 1−4). The blank
experiments illustrated that both the catalyst and base are
essential in affording a desirable yield (entries 5−6). Then, we
tested several conventional bases, and the use of t-BuONa
gave a highest yield (entries 7−10). The solvent screening
indicated that the polar and less-polar solvents were inferior to
toluene (entry 11). Further evaluation of temperature showed
that 120 oC was sufficient for the reaction (entry 12). Thus, the
optimal conditions (standard conditions) are as indicated in
entry 13 when the reaction is conducted at 120 oC.
5jaa,
60%
5aba
, 82%
Ph
Ph
NH
N
NH
5ada,
N
NH
N
NO2
5kaa
, 66%
5gca
, 75%
74%
Ph
CF3
N
O
O
AcO
AcO
NH
N
NH
N
OAc
NH
OMe
OAc
C6F5
Ph
5aea
, 52%
5laa
, 62%
5afa
, 71%
NH
, 68%
N
NH
, 85%
N
NH
, 71%
N
5aga
5aia
5aha
CN
Having established the optimal conditions, we set out to
investigate the substrate scope of the synthetic protocol. As
illustrated in Scheme 2, various quinolines (1a−1l, for their
structures see S1) were initially converted into the quinolinium
salts (3aa−3ai) with alkyl bromides. Then, the reactions of the
salts and 2-aminobezyl alcohol 4a were tested. Gratifyingly,
all the reactions proceeded smoothly and furnished the desired
2-quinolylmethyl anilines in good to excellent yields upon
isolation (5aaa−5aia). Various functionalities (e.g., −F, −Cl,
−Br, ester, −OMe, −SPh, −Me, glycosyl, −CF3) including
reducible ones (−NO2, −CN, alkenyl) on the quinolyl skeleton
and N-alkyl groups were well tolerated. The N-alkyl groups
had little influence on the reaction, whereas the quinolyl
substituents significantly affected the product yields. In
Table 1. Screening of Optimal Reaction Conditionsa
HO
cat., base, solvent
N
temperature
H2N
Br
Ph
NH
N
3aa
4a
5aaa
Ph
entry
1
catalyst
base
5aaa, yield (%)b
67c
[Ru(p-cymene)Cl2]2
Ru3(CO)12
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
-
2
3
4
5
6
7
8
9
5
RuHCl(CO)(PPh3)3
RuCl2(PPh3)3
-
general,
electron-withdrawing
groups
afforded
the
28
-
corresponding products in higher yields (5baa−5faa) than
those of electron-donating groups (5gaa−5jaa), presumably
because the electron-deficient quinolines favor the transfer
hydrogenation process to form the requisite intermediates
(Scheme 1). Noteworthy, structurally complex aromatic
system such as glycosyl-linked quinoline (1l) was also
amenable to the transformation and generated product 5laa in
-
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
8
K2CO3
NaOH
MeONa
8
71
42
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62% yield. This example has demonstrated the potential of the
developed chemistry in modification of sugar derivatives. In
addition to the N-benzyl groups, the alkyl and functionalized
alkyl groups were also compatible with the transformation
(5aha and 5aia).
including 1,7-phenanthroline (1q), 2,3-diphenylpyrido[2,3-
b]pyrazine (1r), 2-phenylpyrido[2,3-d]pyrimidine (1s), and 1-
methyl-1H-pyrrolo[2,3-b]pyridine (1t), were tested. All the
reactions smoothly afforded the desired arylamines in
moderate to good isolated yields (5qaa−5taa). As illustrated
in Scheme 2 and Scheme 3, the developed method has
excellent substrate and functional group compatibility, the
retention of the functionalities offers the potential for
molecular complexity via further transformations.
1
2
3
4
Scheme 3. Variation of Both Coupling Agents
5
6
7
8
HO
R
Br
Ar
3xy
Ar
4z
standard conditions
Ar
Ar
2y
Ar
N
H2N
NH
N
Br
N
1x
5xyz
R
R
Scheme 4. Synthetic applications
One-pot gram-scale synthesis of compound 5aaa
OMe
9
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NH
N
5aac
NH
N
OMe
, 82%
NH
N
5aad
4a
II.
[Ru(p-cymene)Cl2]2 (1 mol %)
t-BuONa (50 mol %),120 o
toluene / t-AmOH = 4:1
(10.6 mmol)
I. toluene
5aab
, 81%
, 76%
5aaa
(1)
110 oC, 12 h
, 65%
Ph
Ph
Ph
N
N
C
1a
(10 mmol)
Br
F
Cl
OMe
MeO
Ph
O
3aa
Ph
Br
I. toluene, 110 oC, 12 h
4a
NH
N
Access to amino acid
NH
N
NH
N
OMe
II.
[Ru(p-cymene)Cl2]2 (1 mol %)
t-BuONa (50 mol %),120 o
toluene/t-amyl alcohol = 4:1
Step 1: one pot synthesis
(1 equiv)
Ph
Ph
Ph
5eag
, 61%
N
5aaf
, 72%
5iae
Br
O
n
, 65%
C
N
N
n = 3
1u
Et
NH
N
N
NH
N
N
Ph
NH
N
N
LiOH (6 equiv)
THF/MeOH/H2O = 3 : 1 : 1
reflux, 4 h
Ph
, 65%
Ph
5mah
, 60%
5aih
5aah
, 68%
N
NH
N
O
N
NH
N
N
S
Step 2
OH
n
Et
(2)
(3)
n
Et
n = 4
5uja
O
6
, 48%
, 95%
n = 4
O
Ph
N
NH
N
Br
Ph
N
NH
N
Ph
N
NH
N
Access to potential biomedical molecules
5maj
, 67%
5mak
Ph
5mai
, 55%
, 55%
Ph
Ph
R1O2C
(2) R2Br, toluene
HO2C
(1) EDC, DMAP
CH2Cl2, r.t.
R1OH
4
then
NH
R2
N
standard conditions
N
O
N
NH
N
N
NH
N
Ph
N
NH
N
CF3
O
N
S
Ph
, 55%
Ph
Ph
5oaa
, 72%
O
5mal
, 47%
O
5naa
N
NH
N
OMe
NH
N
H
Bn
N
NH
N
8
, analogue of adaphostin (NSC 680410) :
PTK inhibitor
N
NH
N
7
, analogue of inhibitor for
PSD95-nNOS proteineprotein
interactions
O
NH
70%
N
N
S
O
Ph
, 63%
Ph
5qaa,
5paa
5oaf
, 68%
Cl
Ph
O
N
O
Ph
Ph
N
N
O
H
H
N
Ph
5saa
N
NH
N
NH
N
NH
48%
N
O
, 45%
5raa,
5taa
, 62%
Ph
Ph
NHBn
9
estradiol benzoate
Ph
Access to free amino aniline and streamline synthesis of drug-relevant product
Subsequently, we turned our attention to the variation of
Pd/C (10 mol%)
, LDA, -70 oC
11
both coupling partners. First, the reactions of various
quinolines (1a, 1e, and 1i) and 2-aminobenzyl alcohols
(4b−4g) were tested. As illustrated in Scheme 3, all the
reaction efficiently afforded the desired product in moderate to
high isolated yields (5aab−5eag). It was found that substrates
4 bearing an electron-donating group on the aryl ring gave
higher product yields (5aab−5aaf) than that of reactant having
a weak electron-withdrawing group (5eag), which is attributed
to the electron-rich 4 favoring the nucleophilic cyclization
process (Scheme 1). However, aliphatic amino alcohols such
as 3-aminopropan-1-ol and 3-amino-3-phenylpropan-1-ol were
not applicable for the transformation, as such substrates
preferentially reacted with the alkyl bromides in the N-
heteroarenium salts. Except for conventional 2-aminobenzyl
alcohols, 2-aminoheteroaryl methanols (4h−4k) were also
effective coupling partners and reacted with quinoline 1a and
1,8-naphthyridine 1m, affording various 2-heteroarylmethyl
arylamines (5aah−5mal). All the 1,8-naphthyridines (1m−1r),
including 2-heteroaryl substituted ones, efficiently coupled
with 2-aminoaryl methanols and generated the diheteroaryl
methanes in good yields (5mah−5oaf), which can serve as
potential hemilabile N-ligands58 and pharmacoactive
molecules such as CYP11B1 inhibitor.59-60 Noteworthy,
pyridine failed to couple with 4a to afford the expected
enamine product, and a complex system was observed.
Further, we tested other types of pyridine-based N-
heteroaromatics. Thus, several representative examples,
5aaa
HCOONH4 (10 eq.)
CH3CH2OH, 75 o
BnHN
N
62%
NH2
N
OH
C
N
10
, 83%
O
(4)
N
11
:
12
Bedaquiline analog (anti-TB drug)
To show the synthetic utility of the developed chemistry, a
gram-scale synthesis of compound 5aaa in satisfactory yield
was achieved by one-pot sequential procedure directly from
quinoline 1a and 2-aminobenzyl alcohol 4a (eq.1 of Scheme
4). Then, the synthetic method could be applied to access
amino acid 6 by successive conversion of 1,8-naphthyridine
1u into 2-alkylamino pyridine 5uja followed by the hydrolysis
of the ester group (eq. 2). Considering the biomedical potential
of N-benzylated benzoic esters, the analogues of analgesics
(compound 7),61-62 PTK inhibitor (compound 8),63 and
antioxidative and antiproliferative agent (compound 9)64 were
efficiently prepared by esterification of quinoline-6-carboxylic
acids with alcohols followed by catalytic conversion of
quinolyl motif to the N-benzyl anilines (eq.3, for details see
Scheme S5-S7). Further, compound 5aaa can undergo
efficient palladium-catalyzed N-dealkylation to afford
synthetically useful −NH2 containing aniline 10 in high yield
(eq. 4, 83%),65-67 and 5aaa was also applicable for direct
synthesis of bedaquiline analog (TMC207), a drug used for the
treatment of pulmonary multi-drug resistant tuberculosis
(MDR-TB) via based-promoted benzylic addition to the
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carbonyl group of compound 11, such a synthesis is far
energy surface and optimized geometries are given in the
Supporting Information (Figures S12 and S13).
superior to the reported protocols that need 4-6 steps.68-69
1
2
3
4
5
6
7
8
9
To gain mechanistic insights into the reaction, several
control experiments were conducted (Scheme 5). Interruption
of the model reaction after 4 h resulted in an allylic amine
3aa-a in 5% yield and 2-aminobenzaldehyde 4a’ in 3% yield
detected by GC-MS (eq. 1 and Figure S1), and the subjection
of compounds 3aa-a and 4a’ under the standard conditions
generated product 5aaa in high yield (eq. 2). Further, the
signals of the carbonyl group in 4a’ (v = 1671 cm-1) and the
C−N bond in 3aa-a (v =1243 cm-1) were detected by in situ IR
analysis (Fig. S10 and 11, SI). These results clearly indicate
that both 3aa-a and 4a’ are the reaction intermediates.
Importantly, treating quinolinium salt 3aa with 4a by
removing the Ru-catalyst from the standard conditions failed
to produce the addition product 5aaa-d (eq. 3), showing that
the reaction initiating with the nucleophilic addition of 4a to
3aa is less likely. Moreover, the reaction of benzylic
deuterated aminoalcohol 4a-d2 and 3aa (also see the reaction
of  or γ-deuterated quinolinium salt with 4a, eq. 5 and eq. 6
of Scheme S2) generated the aniline product 5aaa-dn1 with
different deuterium ratios at the newly formed quinolyl -site
and the benzylic site (eq. 4), which implies that the hydrogen
is transferred from alcohol 4a to the 3aa, and there is a
tautomerization between dihydroquinolines 3aa-a and 3aa-b
(Scheme 1).
The inclusion of t-BuOH and Na+(O1) located above the
reactive center, a double proton-transferred process was found
to be the most facile on the potential energy surface. The
energy barrier of transition state was reduced to 25.3 kcal mol-
1 (ΔG = 23.9 kcal mol-1). Herein, the effects of Na+ on reactive
center respond to the fact that the charge is distributed on both
moieties (Fig. 1).
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59
60
Fig 1. Potential energy surface for the process of 5aaa-c to
5aaa (Relative electronic energies are in kcal mol-1, and the
values in parentheses are free energies)
Scheme 5. Control Experiments
Based on the above findings, a possible reaction pathway
for the formation of product 5aaa is depicted in Scheme 6.
Initially, the ruthenium-catalyzed dehydrogenation16-19, 28-30 of
aminoalcohol 4a under the cooperative actions of base (B-)
followed by hydride transfer ([MH]) to the quinolinium salt
3aa forms the dihydroquinolines (allylic amine 3aa-a and its
tautomer enamine 3aa-b), along with generation of
difunctional agent 4a’ and regeneration of the ruthenium
catalytic species. Then, the coupling between 3aa-b and the
carbonyl group of 4a’ generates the β-alkenyl iminium 5aaa-
b. The subsequent intramolecular nucleophilic cyclization
followed by t-BuOH/Na+ co-assisted C−N bond cleavage of
aminal 5aaa-c gives rise to product 5aaa.
O
OH
standard conditions
(1)
5aaa
18%
N
N
NH2
4 h
NH2
4a
4a'
Bn
Br
Ph
4a'
3aa-a
, 3%
3aa
, 5%
5aaa, 82%
OH
Standard conditions
18 h
3aa-a
(2)
(3)
OH
NH2
standard conditions
N
without [Ru(p-cymene)Cl2]2
N
N
Br
Ph
Ph
H
4a
Bn
3aa
5aaa-d
, 0%
D
D
96% D
16% D
100% D
OH
(4)
N
standard conditions
NH
N
Br
NH2
3aa
4a-d2
Bn 20% D
5aaa-dn1
Scheme 6. Possible pathway for the formation of 5aaa
HO
standard conditions
To better reveal the details of the quinolyl C−N bond
cleavage, the computational study was preformed using the
density functional theory (see computational details in SI).
Figures S12 shows the potential energy profile computed for
the conversion of 5aaa-c to 5aaa, in which all of the structures
were optimized in toluene solution. The results show that the
conversion is a concerted process, including the H-transfer
from N1 to N2 accompanied by the cleavage of C-N bond,
which leads to the aromatization of N1-contained six-
membered ring. This step was calculated to be exothermic by
more than 13 kcal mol-1 (Fig. S12). However, in this figure the
reaction cannot take place in the ground state at room
temperature, since the process has to overcome a barrier of at
least 46 kcal mol-1 (ΔG = 42.5 kcal mol-1). According to the
previous investigation,70-71 this process proceeds with the
assistance of Na+, [RuL]2+ or t-BuOH. We calculated these
effects by adding one explicit Na+, [RuL]2+ or t-BuOH
molecule in the vicinity of the reactive center. The potential
+
N
Br
H2N
4a
NH
N
5aaa
Ph 3aa
Ph
(B-: base)
B-
[Ru]
t-BuOH, Na+
C-N cleavage
hydride
transfer
BH
[RuH]
H+
- H2O
O
+
- H+
N
H2N
Ph
N
N
N
H
H2N
cyclization
Ph
Ph
3aa-b
4a'
5aaa-c
5aaa-b
In summary, by a strategy merging hydrogen transfer and
selective coupling, we have demonstrated catalytic
a
conversion of N-heteroaromatics to functionalized arylamines
with 2-aminoaryl methanols in the presence of a [Ru(p-
cymene)Cl2]2/t-BuONa system. The reaction is achieved via
initial formation of N-heteroarenium salts followed by
sequential functionalization of the N-heteroaryl β and -sites
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Efficient and General Synthesis of Primary Amines by Ruthenium-
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Manganese-Catalyzed alpha-Alkylation of Ketones, Esters, and
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Amines Directly from Alcohols and Ammonia. Angew. Chem. Int. Ed.
2008, 47, 8661-8664.
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Manganese-Catalyzed Dehydrogenative Alkylation or -Olefination of
Alkyl-Substituted N-Heteroarenes with Alcohols. Angew. Chem. Int.
Ed. 2018, 57, 9131-9135.
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Alkylation of Secondary Alcohols with Primary Alcohols via
Borrowing Hydrogen/Hydrogen Autotransfer. Chem. Eur. J. 2017, 23,
12110-12113.
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Alkylation of Unactivated Amides and Esters with Alcohols. J. Am.
Chem. Soc. 2016, 138, 10786-10789.
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Alkylation of Aromatic Amines by Alcohols. Angew. Chem. Int. Ed.
2015, 54, 15046-15050.
and a C−N bond cleavage, proceeding with the striking
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features of broad substrate scope, excellent functional groups
tolerance, high chemo-selectivity and atom-efficiency, and
applicable for streamline synthesis of potential biomedical
molecules. The work presented offers a practical platform for
structural modification of non-activated N-heteroaromatics,
and enables to produce novel products that are inaccessible or
difficult to prepare with the conventional approaches. The
applied strategy is anticipated to spur the enthusiasm toward
the development of new catalytic transformations of inert
organo-systems to functional frameworks.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: minzhang@scut.edu.cn
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures including spectroscopic and
analytical data, this material is available free of charge via the
internet at http://pubs.acs.org.
ACKNOWLEDGMENT
The authors are grateful to the financial support of the National
Key Research and Development Program of China
(2016YFA0602900), National Natural Science Foundation of
China (21971071), Guangdong Province Science Foundation
(2017B090903003), 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).
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Catalytic Conversion of N-Heteroaromatics to Functionalized Arylamines
ACS Paragon Plus Environment