Ortho-C–H addition of 2-substituted pyridines with alkenes and imines enabled by mono(phosphinoamido)-rare earth complexes

Article abstract of DOI:10.1002/aoc.6345

We here reported a special catalytic performance of mono(phosphinoamido)-ligated rare earth complexes in ortho-C–H functionalization of pyridines with nonpolar alkenes and polar imines. Upon treatment with one equiv. of borate reagent B(C₆F₅)₃ or [Ph₃C][B(C₆F₅)₄], complex NP1-Sc can act as an efficient catalyst for ortho-C–H alkylation of pyridines towards alkenes. In the presence of 1:1 mixed secondary amine of HN (SiMe₃)₂ and HNBn₂, complex NP2-Gd can catalyze ortho-C–H addition of pyridines towards imines, effectively. A wide range of substrates were subjected to the catalysis to render the one step synthesis of a variety of ortho-alkylated and ortho-aminoalkylated pyridine derivatives in good yields and an excellent regioselectivity and chemoselectivity.

Full text of DOI:10.1002/aoc.6345

Received: 1 April 2021
DOI: 10.1002/aoc.6345
Revised: 9 June 2021
Accepted: 11 June 2021
R E S E A R C H A R T I C L E
Ortho-C–H addition of 2-substituted pyridines with alkenes
and imines enabled by mono(phosphinoamido)-rare earth
complexes
Hailong Lin1
Tao Jiang1
| Yongrui Li1
| Jing Li2 | Yanhui Chen1
| Jinyu Wang1
| Mei Zhang1
|
1College of Chemical Engineering and
Materials Science, Tianjin University of
Science and Technology (TUST), Tianjin,
China
2College of Food Science and Engineering,
Tianjin University of Science and
Abstract
We here reported a special catalytic performance of mono(phosphinoamido)-
ligated rare earth complexes in ortho-C–H functionalization of pyridines with
nonpolar alkenes and polar imines. Upon treatment with one equiv. of borate
reagent B(C6F5)3 or [Ph3C][B(C6F5)4], complex NP1-Sc can act as an efficient
catalyst for ortho-C–H alkylation of pyridines towards alkenes. In the presence
of 1:1 mixed secondary amine of HN (SiMe3)2 and HNBn2, complex NP2-Gd
can catalyze ortho-C–H addition of pyridines towards imines, effectively.
A wide range of substrates were subjected to the catalysis to render the one
step synthesis of a variety of ortho-alkylated and ortho-aminoalkylated
pyridine derivatives in good yields and an excellent regioselectivity and
chemoselectivity.
Technology (TUST), Tianjin, China
Correspondence
Yanhui Chen, College of Chemical
Engineering and Materials Science,
Tianjin University of Science and
Technology (TUST), 29 13th Avenue,
TEDA, Tianjin, 300457 China.
Email: cyh@tust.edu.cn
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21371131
K E Y W O R D S
alkenes, C–H activation, imines, pyridine, rare earth
1 | INTRODUCTION
addition/reductive elimination. In addition, some alkyl zir-
conium and organo-rare earth complexes could also serve
The elaboration of pyridine ring continues to be an active
issue in synthetic chemistry, mainly due to the prevalence
of pyridine in natural products, bioactive molecules,
ligands, and functional materials.[1] Among the various
synthetic strategies reported, the C–H functionality of
pyridine mediated by organometallics is highly desirable
in terms of its atom- and step-economy.[2] In particular,
the catalytic C–H addition of pyridines towards unsatu-
rated chemical bonds offers the most straightforward
synthesis of alkylated pyridines with a 100% atom-
efficiency.[3–9] Therefore, much effort has been devoted to
this area. Late transition metal complexes, such as Rh,[3b,f,h]
Co,[3i,k] Ni,[3c–e,l,n] Cr,[3m] and Ru,[3a,j] have been
reported to catalyze C–H alkylation of pyridines with
nonpolar alkene (or alkyne) to give ortho-, meta-, and
para-substituted pyridines via a coupling of oxidative
as efficient catalysts for ortho-C–H alkylation of pyridines
with olefins through a σ-bond metathesis pathway.[5,6] In
1989, Jordan and co-workers pioneered the catalytic
ortho-C–H addition of pyridine with propene by use of a
zirconium bismetallocene under H2 atmosphere.[5a]
Subsequently, Teuben et al. found
a metallocene
yttrium complex, which can also be used as catalyst for the
ortho-C–H alkylation of pyridine with ethylene at high
reaction temperature and ethylene pressure.[6a] Recently,
Hou and co-workers developed a combination of a half-
sandwich scandium complex (Scheme 1a) and B(C6F5)3,
which indicates high catalytic activity for ortho-C–H func-
tionalization of pyridines with various olefins including
norbornene, styrene, allenes, and α-olefins.[6b–d]
In contrast to the numerous reports about the C–H
functionalization of pyridine with nonpolar alkene and
Appl Organomet Chem. 2021;e6345.
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https://doi.org/10.1002/aoc.6345

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LIN ET AL.
SCHEME 1 Rare earth complexes for ortho-C–H addition of pyridines towards olefins or imine
alkyne, the successful examples towards polarized π
bonds are relatively scarce. Although a lot of work on cat-
alytic C–H transformation of 2-arylpyridines into C = X
(X = O, N) bonds has been extensively explored, in most
cases, the C–H activation only occurs at arene ring rather
than at the pyridine core.[7] In 2011, Shi et al. reported
the nucleophilic addition of pyridines to aldehydes
via a Ir-catalyzed meta-C–H activation of pyridine.[4b]
Mindiola et al. demonstrated scandium-mediated ortho-
C–H functionalization of pyridine with 2-isocyano-
1,3-diisopropylbenzene.[8] Just recently, the first example
for ortho-C–H addition of pyridines towards imines was
also realized by Mashima and co-workers.[9a,b] Some
amido-rare earth complexes, such as Gd[N (SiMe3)2]3
(Scheme 1b), were found to be catalytically active for an
insertion of nonactivated imines into the ortho-C–H bond
of 2-substituted pyridines.[9a] Despite the fast-paced
advances in C–H functionalization of pyridines towards
various unsaturated bonds by a variety of catalysts, as far
as we are aware, few organometallics have catalytic
behavior for both nonpolar alkenes and polar imines in
the ortho-C–H transformation of pyridines.
mono(phosphinoamido)-rare earth complexes. We found
that the combination of scandium complex NP1-Sc and
B(C6F5)3 was highly efficient catalyst for ortho-C–H alkyl-
ation of 2-substituted pyridines towards higher olefins
including norbornene, styrenes, α-olefins, and even
α,ω-dienes. With an assist of 1:1 mixed secondary amine of
HN (SiMe3)2 and HNBn2, gadolinium complexes such as
NP2-Gd are also highly effective for catalytic ortho-C–H
aminomethylation of pyridines towards polar imines with
formation of ortho-aminoalkylated pyridine derivatives. A
wide range of substrates were tested, and good yields as
well as excellent regioselectivity and chemoselectivity were
obtained. In addition, the deuterium-labeling experiments
were also conducted and the results indicated that
the alkylation reaction of pyridines underwent a rare
earth-mediated ortho-C–H activation.
2 | EXPERIMENTAL
2.1 | General procedures and materials
For many years, we have been drawing considerable
attention in the synthesis and catalytic application of novel
rare earth complexes. Intrigued by the special bidentate
property of phosphinoamide ligand as well as its partial
N–P multiple-bonding character,[10–12] we recently suc-
cessfully prepared the first mono(phosphinoamido)-ligated
rare earth dialkyl complexes and found that scandium
complex (Scheme 1c) combined with one equiv. of
All manipulations were routinely carried out under a dry
and oxygen free nitrogen atmosphere by using standard
Schlenk-line techniques or using a glovebox. Samples
(organo-rare earth complexes) for NMR spectroscopic
measurements were prepared in the glovebox by use of
1
J. Young valve NMR tubes. H, 13C, and 31P spectra were
recorded on a JEOL-AL400 or AscendIII-400 (BRUKER)
spectrometer. Elemental analyses were performed by a
1
B(C6F5)3
could
effectively
catalyze
cyclization/
MICRO CORDER JM10. H NMR (400 MHz) and 13C
hydroarylation of 1,5-diene with pyridine, directly
rendering the synthesis of pyridyl-functionalized cis-
1,3-disubstituted cyclopentane derivatives with high
diastereoselectivity.[13a] However, their catalytic applica-
tion in C–H functionalization of pyridines with other π
electrophiles has still remained unexplored. Herein, we
decided to explore the feasibility of catalytic ortho-C–H
addition of pyridines towards alkenes and imines by use of
NMR (100 MHz) spectra for alkylation pyridine products
were recorded on AscendIII-400 (BRUKER) spectrometer.
Data were reported as follows: chemical shift in ppm (δ),
multiplicity
(s = singlet,
d = doublet,
t = triplet,
q = quartet, m = multiplet, br = broad signal), coupling
constant (Hz), and integration. GC/MS data were
obtained on a GC/MS4000 (VARIAN). High-resolution
MS were obtained on a LCMS-IT-TOF (SHIMADZU).

LIN ET AL.
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Gas chromatography analysis was performed on Agilent
Technologies 7890A GC System.
2.3 | A typical procedure for ortho-C
(sp2)–H addition of 2-substituted pyridines
All solvents used were dried and distilled over an
appropriate drying agent under nitrogen. The secondary
amines NHBn2 and NH (SiMe3)2, pyridines (1a–1m), and
olefins (2a–2o) were purchased from J&K® or TCI
and dried over CaH2, vacuum-transferred, degassed by
two freeze-pump-thaw cycles and kept in a glovebox.
Anhydrous rare earth chloride (LnCl3) used were
purchased from REO. [Ph3C][B(C6F5)4] and B(C6F5)3
were obtained from Tosoh Finechem Corporation and
used without purification. Imines (4a–4j) were prepared
according to the literature by the reaction of aldehydes
and corresponding amines.[9] Phosphinoamines includ-
ing NHP1-NHP4, Ln-(CH2C6H4NMe2-o)3 (Ln = Sc, Y,
Gd, Lu, Sm, Ho), and mono(phosphinoamido)-rare earth
complexes NP1-Ln (Ln = Sc, Y, Lu), NP2-Sc, NP3-Sc,
and NP4-Sc were prepared according to the
literature.[13a,14,15]
with alkenes
A chlorobenzene solution (1.0 ml) of B(C6F5)3 (20.4 mg,
0.04 mmol) was slowly dropped into a stirred chloroben-
zene solution (1.0 ml) of NP1-Sc (27.0 mg, 0.04 mmol) in
a 20-ml Schlenk tube. Then 2-substituted pyridine
1 (1.0 mmol), alkene 2 (4.0 mmol) was added in the reac-
tion system. The Schlenk tube was sealed and taken out
of the glovebox and headed at 100ꢁC with magnetic stir-
ring. The reaction was monitored by TLC. After the reac-
tion was completed, the mixture was cooled to room
temperature and purified directly by silica gel column
chromatography (hexane/EtOAc = 20/1) to afford
alkylation pyridine 3. The yield of 3 was calculated
based on 1.
2.4 | A typical procedure for ortho-C
(sp2)–H addition of 2-substituted pyridines
with imines
2.2 | Synthesis of
mono(phosphinoamido)-rare earth dialkyl
complexes
To a solution of complex NP2-Gd (35.8 mg, 0.05 mmol,
10 mol%) in 2-ml toluene was added N,N-dibenzylamine
As shown in Scheme 2, a THF (5 ml) solution of
NH-P2 ligand (0.45 g, 1.53 mmol) was added
dropwise into a solution of Y (CH2C6H4NMe2-o)3
(0.75 g, 1.53 mmol) in THF (10 ml), and the mixture
was stirred for about 2 h at ambient temperature.
After removing the solvent under reduced pressure, the
residue was washed by hexane (5 ml ꢀ 2) to obtain a
pale-yellow powder NP2-Y (0.86 g, 1.06 mmol, 87%
yield). The crystals of NP2-Y suitable for X-ray analysis
were obtained from toluene solution layered with
hexane. According to the same procedure, complexes
NP1-Sm, NP1-Ho, NP1-Gd, NP2-Y, NP3-Y, NP4-Y,
NP2-Lu, and NP2-Gd were also obtained. These
complexes are stable in solvent and fully characterized
by spectroscopy and X-ray crystallography.[16,17]
(9.3
hexamethyldisilazane (11.4 μl, 0.05 mmol, 10 mol%),
2-substituted pyridine (0.5 mmol), and imine
μl,
0.05 mmol,
10
mol%),
1,1,1,3,3,3-
1
4 (1.0 mmol) in a 20-ml Schlenk tube. The Schlenk tube
was sealed and heated at 100ꢁC with magnetic stirring.
The reaction was monitored with TLC. After the reaction
was completed, the reaction mixture was cooled to room
temperature, diluted with Et2O (1.5 ml), and filtered
through a short silica gel plug. The obtained solution was
concentrated under reduced pressure at 100ꢁC for at
least 1 h to remove starting materials. The residue
was purified by silica gel column chromatography
(Hexane/EtOAc = 10/1) to give aminoalkylation pyridine
5. The yield of 5 was calculated based on 1.
3 | RESULTS AND DISCUSSION
3.1 | The typical solid structures of
mono(phosphinoamido)-rare earth dialkyl
complexes
The typical solid structures of yttrium complexes NP2-Y
and NP4-Y are shown in Figure 1. A unique η2–N–P
coordination to yttrium center and σ–Y–N bond (NP2-Y:
Y1-N1 2.302(2) Å, NP4-Y: Y1-N1 2.263(4) Å) are uncov-
ered in the molecular structures. The relatively short N–P
bond distance in these complexes (NP2-Y: 1.679(2) Å,
SCHEME 2 Synthesis of mono(phosphinoamido)-rare earth
dialkyl complex

4 of 10
LIN ET AL.
FIGURE 1 ORTEP drawings of
NP2-Y (left) and NP4-Y (right) with 30%
thermal ellipsoids. H atoms have been
omitted for clarity. Selected bond lengths
(Å) for NP2-Y: Y1-N1 2.302(2), Y1-C28
2.427(3), Y1-C19 2.449(3), Y1-N2 2.498
(2), Y1-N3 2.561(2), Y1-P1 2.7385(8),
N1-P1 1.679(2). Selected bond lengths
(Å) for NP4-Y: Y1-N1 2.263(4), Y1-C22
2.443(5), Y1-C33 2.427(5), Y1-N2 2.501
(4), Y1-N3 2.535(4), Y1-P1 2.8048(15),
N1-P1 1.657(4)
TABLE 1 Optimization of the
reaction conditions[a]
Entry
[Ln]
[B]
t/h
Yield [%]
3aa
-
3aa0
1
NP1-Sc
-
-
24
24
1
-
2
B(C6F5)3
B(C6F5)3
[Ph3C][B(C6F5)4]
[Ph3C][B(C6F5)4]
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
-
-
3
NP1-Sc
NP1-Sc
NP1-Sc
NP2-Sc
NP3-Sc
NP4-Sc
NP1-Y
98
90
-
-
4
0.5
6
5
99
-
5
6
1
97
97
34
12
24
12
20
14
97
95
99
-
7
1
-
8
1
-
9
24
24
24
24
24
2
-
10
11
12
13
14[b]
15[c]
16
17
18
NP1-Lu
NP1-Sm
NP1-Ho
NP1-Gd
NP1-Sc
NP1-Sc
η 5-Cp*-Sc
Y[N (SiMe3)2]3
Sc[N (SiMe3)2]3
-
-
-
-
-
2
-
4
-
24
24
-
-
-
aReaction conditions: [Ln] = mono(phosphinoamido)-rare earth complex (0.04 mmol), [B] = borate reagent
(0.04 mmol), 1a (1.0 mmol), 2a (4.0 mmol, 4.0 equiv), chlorobenzene (2 ml), yields of 3aa and 3aa0 were
determined by GC with mesitylene as an internal standard.
bToluene as solvent (2 ml).
cBenzene as solvent (2 ml).

LIN ET AL.
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NP4-Y: 1.657(2) Å) suggests partial N–P multiple-
the synthesis of alkylated pyridine derivatives. The spe-
cial η2-chelating mode and partial N–P multiple-bonding
character in the mono(phosphinoamido)-rare earth com-
plex partly resemble to the η5-fashion of Cp ligand in
half-sandwich rare earth catalyst, which intensively
encouraged us to explore its catalytic feasibility in
ortho-C–H addition of pyridines towards olefins. As
shown in Table 1, the ortho-C–H alkylation of 2-picoline
with norbornene was chosen as a model reaction for
bonding character.[13a,18]
3.2 | Rare earth-catalyzed ortho-C–H
addition of pyridines with alkenes
The C–H alkylation of pyridine with alkenes provides a
most straightforward and 100% atom-efficient route for
TABLE 2 Scope of pyridines and olefins[a,b]
aReaction conditions: NP1-Sc (0.04 mmol), B(C6F5)3 (0.04 mmol), 1 (1.0 mmol), 2 (4.0 mmol), and chlorobenzene (2 ml).
bIsolated yields.
cNP1-Sc (0.06 mmol), B(C6F5)3 (0.06 mmol).

6 of 10
LIN ET AL.
testing. The reaction was carried out in chlorobenzene at
100ꢁC with 4.0 mol% catalyst loading. Neither the natural
scandium complex NP1-Sc nor B(C6F5)3 used alone was
ineffective, while the combination of NP1-Sc/B(C6F5)3
was highly efficient, and the catalytic reaction was
accomplished in only 1 h with the formation of the alkyl-
ation product 3aa in 98% yield (entries 1–3). These results
suggest the cationic scandium alkyl species, generated in
situ from the reaction of NP1-Sc with borate reagent, is
essential for this transformation.[6b–d,13a] Upon replacing
B(C6F5)3 with [Ph3C][B(C6F5)4], a higher catalytic effi-
ciency was achieved. The alkylation product 3aa was
obtained in 90% yield accompanied with a little amount
of product 3aa0 in 0.5 h. The formation of bialkylation
product 3aa0 indicated that the 2-pyridymethyl C(sp3)–H
of 2-picoline was also alkylated by this catalysis.
Notably, when the reaction time was extended to 6 h, the
bialkylation product 3aa0 was yielded quantitatively
(entries 4–5). Further experiments disclosed that the sub-
stituents on the phosphorus atom of the phosphinoamide
anion had a much lower influence on the catalyst activity
than those on nitrogen atom (entries 3 and 6–8). As a
contrast, analogous yttrium complex NP1-Y, lutetium
complex NP1-Lu, samarium complex NP1-Sm, holmium
complex NP1-Ho, and gadolinium complex NP1-Gd are
less effective (entries 9–13). The reaction in toluene or
benzene could also proceed well (entries 14 and 15).
Employing η5-Cp*-Sc/B(C6F5)3 as catalyst under the
same conditions, the reaction was completed in 4 h
with the quantitative yield of 3aa (entry 16). Triamido-
rare earth complexes, such as Sc[N (SiMe3)2]3 and Y
[N (SiMe3)2]3, were unactive, which implied that the
σ–Ln–C bond plays an important role for C–H alkylation
of pyridine towards olefins (entries 17 and 18).
sequence.[13] In the cases of 1,6-heptadiene (2j) and
1,7-octadiene (2k), acyclic adducts were formed as main
products so that a free C=C double bond remained
(see 3aj in 78% yield and 3ak in 84% yield).[19] Similar
to the cationic half-sandwich scandium catalyst, the
ortho-C–H alkylation of pyridine towards styrene
furnished a linear alkylation product 3al in 94% yield. This
should be attributed to the 1,2-insertion of Sc–C into
styrene.[6b] As a contrast, late-transition metal catalysts
usually produce a branched additive product via a
2,1-insertion mode.[3d,i,k,m] Under the same conditions,
substituted styrenes such as 4-methyl- and 4-halogen
styrenes were all well tolerated (see 3am–3ao in 90–95%
yields). Subsequently, we examined the scope of pyridines
with styrene as partner. 2,3-Dimethyl-, 2,4-dimethyl-,
3-bromo-2-methyl-, 2-ethyl-, 2-isopropyl-, 2-tert-butyl-, and
2-phenyl-substituted pyridines were all alkylated by
styrene to generate linear alkylation products 3bl–3hl
in high yields. It is noteworthy that the C–H alkylation
of 2-phenylpyridine only took place at the ortho-position
of the pyridine unit rather than on the phenyl ring. The
ortho-C–H alkylation of 5,6,7,8-tetrahydroquinoline (1i)
and 8-methyl-5,6,7,8-tetrahydroquinoline (1j) towards sty-
rene could also proceed well. Unfortunately, simple pyri-
dine as well as quinoline was ineffective for this catalysis.
All of these experimental results indicated that the cata-
lytic performance of current mono(phosphinoamido)-
scandium catalyst is comparable with that of half-
sandwich scandium catalyst reported.[6b–d]
3.3 | Rare earth-catalyzed ortho-C–H
addition of pyridines towards imines
With the optimal reaction conditions in hand, we next
examined the scopes of pyridines and olefins with the
combination of NP1-Sc/B(C6F5)3 as catalyst. As indicated
in Table 2, a series of olefins was first tested with
2-picoline as C–H partner. Besides norbornene, linear
α-alkenes with a formula of CH2 = CH2CnH2n+1 (n = 4,
6, 8, 10, and 12) were also compatible with this catalytic
protocol, and the branched alkylation pyridine products
3ab–3af were obtained in 81–92% yields in 15 h. The for-
mation of branched addition products 3ab–3af suggests
that a 2,1-insertion of Ln–C bond into α-olefins occurs in
the catalytic cycle,[6b,13a] which contrasted with the linear
adductive products by late-transition metal catalyst in a
1,2-insertion fashion.[3b,d,i,l] Allyltrimethylsillane (2g) and
allylbenzene (2h) were effective substrates (See 3ag in 83%
yield and 3ah in 92% yield). α,ω-Dienes were also suitable
for this catalytic protocol. 1,5-Hexadienes (2i) was
converted into the cyclic product 3ai as a single cis-isomer
in 94% yield via a cascade 2,1-insertion of alkene
Recently, triamido-rare earth complexes, such as Gd
[N (SiMe3)2]3 (Scheme 1b), were demonstrated
to be catalytically active for ortho-C–H addition of
2-substituted pyridines towards imines with the formation
of ortho-aminomethylation pyridine derivatives. In
this catalytic process, the σ-amido-rare earth bond
undoubtedly plays an important role. Considering the
σ-amido-rare earth bond in these mono(phosphinoamido)-
rare earth complexes,[9a,b] we next decide to explore the
probability of catalytic ortho-C–H addition of pyridine
into polar C=N double bond of imines by use of
mono(phosphinoamido)-rare earth complexes.
As shown in Table 3, the ortho-C–H addition reaction
of pyridine 1h with N,1-dicyclohexylmethanimine (4a)
was chosen as model reaction for checking, and the
reaction was conducted in toluene at 100ꢁC for 12 h. We
first explored the influence of second amine on the reac-
tion in the presence of 5.0 mol% of NP1-Y. No conversion
took place without addition of any second amine

LIN ET AL.
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TABLE 3 Optimization of the
reaction conditions[a]
Entry
[Ln]
Additive 1
-
Additive 2
-
Yield 5ha (%)
1
NP1-Y
NP1-Y
NP1-Y
NP1-Y
-
2
NH (SiMe3)2
NHBn2
NH (SiMe3)2
NHBn2
NHBn2
NHBn2
NHBn2
NHBn2
NHBn2
NHBn2
NHBn2
HNBn2
HNBn2
HNBn2
31
3
23
4
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
NH (SiMe3)2
-
36
5
NP2-Y
42
6
NP3-Y
35
7
NP4-Y
34
8
NP2-Sc
trace
20
9
NP2-Lu
NP2-Gd
NP2-Gd
Gd[N (SiMe3)2]3
η 5-Cp*-Y
10
11[b]
12[d]
13
88
97(93)[c]
90[c]
-
NH (SiMe3)2
aReaction conditions: [Ln] = organo-rare earth complex (0.025 mmol), additive 1 (0.025 mmol), additive 2
(0.025 mmol), 1 h (0.5 mmol), 4a (0.75 mmol, 1.5 equiv.), 100ꢁC, 12 h, toluene (2 ml). The yields of 5ha was
determined by GC with mesitylene as an internal standard.
b4a(1.0 mmol).
cIsolated yield.
dGd[N (SiMe3)2]3 (10.0% mol), HNBn2 (10.0%mol), 24 h (See Nagae et al.[9a]).
(entry 1). A small amount of alkylation product 5ha was
detected when 10 mol% NH (SiMe3)2 or NHBN2
was added into the reaction system (entries 2–3). In the
presence of a mixture of secondary amines NH (SiMe3)2
(5 mol%) and NHBN2 (5 mol%), the yield of 5ha was
increased up to 36% (entry 4). Then, a series of various
mono(phosphinoamido)-yttrium complexes were tested
and found no increment in yield (entries 4–7). The analo-
gous scandium and lutetium were also less catalytically
efficient (entries 8–9). To our delight, when analogous
gadolinium complex NP2-Gd was employed under the
same reaction conditions, the yield of 5ha was rocketed
to 88% (entry 10). Remarkably, upon employing 2.0
equiv. amount of 4a, 5ha was obtained in 97% yield
(entry 11). As contrast, the reported combination of Gd
[N (SiMe3)2]3 (10 mol%)/HnBn2 (10 mol%) gave a 90%
yield of 5ha in 24 h[9a] (entry 12). The half-sandwich rare
earth complexes η5–Cp*–Y was less effective under the
same conditions (entry 13). Loading 10 mol% of complex
NP2-Gd accompanied with equimolar amount of NH
(SiMe3)2 and NHBN2, we next scrutinized various pyri-
dines and imines, as showed in Table 4. With 1h as C–H
partner, we first checked the scope of imines. The imine
with an isopropyl, pentan-3-yl, or cyclopentyl group at
the imine carbon atom reacted with 1 h to give the
corresponding aminomethylation products 5hb–5hd in a
good yield. When the more hindered tert-butyl
unit was introduced onto imine carbon atom, the
aminomethylation reaction gave low conversion (see 5he
in 22% yield). This is presumably due to the steric hin-
drance that impedes the insertion of Gd–C bond into
C=N double bond of imine to some extent. In contrast,
the imines anchoring a tert-butyl group at nitrogen atom
led to a good yield (see 5hh in 61% yield). In a similar
manner, substituents at nitrogen atom of imine, such as
isopropyl, cyclopentane, 1-phenylethyl, and even
2-adamantyl, are all well tolerated, and the addition
products were obtained in good yield (see 5hf, 5hg, 5hi,
and 5hj). Unfortunately, when a primary alkyl was
attached to the carbon or nitrogen atom of imine, the
related catalysis is less efficient, probably because of
the stronger interaction between the formed
aminomethylation product and metal center.[9a,b]
With imine 4a as model substrate, a series of
2-substituted pyridines were evaluated in this catalysis.
The aminomethylation reaction of 2-ethyl-(1e),

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LIN ET AL.
TABLE 4 Scope of pyridines and imines[a,b]
SCHEME 3 Deuterium-labeling experiments
selectively occurred at 2-position of quinoline ring with-
out modifying C–H in 8-position. Benzo[h]quinoline
(1m) could also be aminomethylated, effectively
(see 5ma in 80% yield).
aReaction conditions: NP2-Gd (0.05 mmol), NH (SiMe3)2 (0.05 mmol),
NHBn2 (0.05 mmol), 1 (0.5 mmol), 4 (1.0 mmol), 100ꢁC, toluene (2 ml).
bIsolated yields.
3.4 | Deuterium-labeling experiments
c20 mol% catalyst loading.
In order to get some mechanistic insight into this C–H
transformation by rare earth catalyst, deuterium-labeling
experiments were carried out under the standard condi-
tions. As shown in Scheme 3, the reaction of 1h-D9 with
1-octene (2c) indicated that the ortho-deuterium atom of
pyridine 1h-D9 was transferred to the expected methyl
unit of alkylation product 3hc-D9, which implied a pyri-
dine ortho-C–H cleavage process in the catalysis cycle
(Equation 1).The competitive and parallel reactions of 1h
and 1h-D9 with 1-octene gave a kinetic isotope effect
(KIE) value of kH/kD = 3.5 and 4.6, respectively,
suggesting that the C–H bond activation (deprotonation)
should be involved in the rate determining steps for the
current catalysis (Equations 2 and 3).
2-isopropyl-(1f), and 2-tert-butyl-(1g) pyridines could be
readily aminomethylated with moderate to good yields of
isolation product (see 5ea, 5fa, and 5ga, 51–81% yields).
The ring-fused 5,6,7,8-tetrahydroquinoline and 8-methyl-
5,6,7,8-tetrahydroquinoline are also effective substrates
(see 5ia and 5ja). Notably, the aminomethylation of
quinolines could also proceed efficiently by this catalysis
with the formation of quinoline derivatives 5ka and
5la in 62% and 61% yields, respectively. It is
noteworthy that the C–H alkylation of quinolines

LIN ET AL.
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4 | CONCLUSIONS
[2] Some reviews for C–H functionality of pyridines: a) Y. Nakao,
Synthesis 2011, 20, 3209; b) D. A. Colby, A. S. Tsai, R. G.
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In summary, we have demonstrated for the first time that
mono(phosphinoamido)-rare earth complexes, such as
NP1-Sc and NP2-Gd, can serve as efficient catalyst
precursors for ortho-C–H addition of pyridines with
nonpolar alkenes and polar imines with an excellent
regioselectivity and chemoselectivity. A broad range of
substrates were subjected to the current catalysis, directly
rendering the synthesis of a variety of ortho-alkylation
and ortho-aminoalkylated pyridine derivatives in moder-
ate to excellent yields and with a 100% atom-efficiency.
The behaviors of current catalyst are comparable
to those of half-sandwich rare earth catalyst along
with amido-rare earth catalyst reported previously. The
key to the success of mono(phosphinoamido)-rare earth
complexes may be attributed to its special η2-coordiantion
of N-P to rare earth site as well as its unique σ-amido-
rare earth bond. Further research on the catalytic
applications of the mono(phosphinoamido)-rare earth
complexes in other chemical transformations are now
in progress.
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ACKNOWLEDGMENT
This work was financially supported by the National
Natural Science Foundation of China (no. 21371131).
AUTHOR CONTRIBUTIONS
Hailong Lin: Data curation. Yongrui Li: Methodology.
Jinyu Wang: Investigation. Mei Zhang: Formal
analysis. Tao Jiang: Funding acquisition; supervision.
YanHui Chen: Funding acquisition; supervision.
[4] Two examples for C–H functionality of pyridines towards
polar multiple bonds by late-transition metal catalysts: a) E. J.
Moore, W. R. Pretzer, T. J. O'Connell, J. Harris, L. LaBounty,
L. Chou, S. S. Grimmer, J. Am. Chem. Soc. 1992, 114, 5888;
b) B. J. Li, Z. J. Shi, Chem. Sci. 2011, 2, 488.
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towards olefins by rare-earth catalysts: a) B. Deelman, W.
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Boronin, A. V. Cherkasov, G. K. Fukin, A. S. Shavyrin, A. A.
Trifonov, Adv. Synth. Catal. 2020, 362, 5432.
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are
available in the supporting information of this article.
ORCID
Hailong Lin https://orcid.org/0000-0002-3454-0246
Yongrui Li https://orcid.org/0000-0002-1522-044X
Jinyu Wang https://orcid.org/0000-0002-3714-8733
Mei Zhang https://orcid.org/0000-0002-5767-7421
Tao Jiang https://orcid.org/0000-0002-9854-7228
Jing Li https://orcid.org/0000-0003-3338-0284
Yanhui Chen https://orcid.org/0000-0002-6293-535X
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SUPPORTING INFORMATION
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in the Supporting Information section at the end of this
article.
How to cite this article: H. Lin, Y. Li, J. Wang,
M. Zhang, T. Jiang, J. Li, Y. Chen, Appl Organomet
Chem 2021, e6345. https://doi.org/10.1002/aoc.
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