Direct ortho-C-H Aminoalkylation of 2-Substituted Pyridine Derivatives Catalyzed by Yttrium Complexes with N,N′-Diarylethylenediamido Ligands

Article abstract of DOI:10.1021/jacs.8b03998

A mixed ligated amidoyttrium complex, Y(NBn₂)(L1)(THF)₂ (8, L1 = N,N'-bis(2,6-diisopropylphenyl)ethylenediamine), served as a catalyst for addition of the ortho-pyridyl C(sp²) - H bond of 2-substituted pyridines to nonactivated imines; complex 8 showed superior catalytic performance compared with Y[N(SiMe₃)₂]₃ (1) and Y[N(SiMe₃)₂]₂(NBn₂)(THF) (2). Concerning the reaction mechanism, we conducted a stoichiometric reaction of an alkylyttrium complex, Y(CH₂SiMe₃)(L1)(THF)₂ (7), with 2-ethylpyridine (4e), giving a mixture of (η³-pyridylmethyl)yttrium complex 9 and (η²-pyridyl)yttrium complex 10 along with elimination of SiMe₄. Furthermore, addition of N-(tert-butyl)-2-methylpropan-1-imine (5i) to the mixture of 9 and 10 afforded (pyridylmethylamido)yttrium complex 11 as a single product, and the catalytic activity of 11 was comparable to that of complex 8. Kinetic analysis of the aminoalkylation reaction in the presence/absence of HNBn₂ revealed that the reaction rate in the presence of HNBn₂ was four times faster than that without HNBn₂ due to acceleration of the product-eliminating step from complex 11 by HNBn₂ to regenerate amidoyttrium complex 8 and the product. In addition, we determined that the catalytic reaction obeyed a first-order rate dependence on the catalyst concentration, independent of the imine concentration, and a second-order rate dependence on the concentration of the pyridine substrate in the reaction system, both with and without HNBn₂. An enantiomerically pure N,N'-diaryl-1,2-diphenylethylenediamido ligand was applied for the C(sp²) - H aminoalkylation reaction in combination with Lu(CH₂SiMe₃)₃(THF)₂ to give chiral aminoalkylated products in moderate yield with good enantioselectivity.

Full text of DOI:10.1021/jacs.8b03998

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Article
Direct ortho-C—H Aminoalkylation of 2-Substituted Pyridine Derivatives
Catalyzed by Yttrium Complexes with N,N#-Diarylethylenediamido Ligands
Abhinanda Kundu, Mariko Inoue, Haruki Nagae, Hayato Tsurugi, and Kazushi Mashima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03998 • Publication Date (Web): 18 May 2018
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Direct ortho-C—H Aminoalkylation of 2-Substituted Pyridine
Derivatives Catalyzed by Yttrium Complexes with N,Nʹ-Dia-
rylethylenediamido Ligands
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Abhinanda Kundu, Mariko Inoue, Haruki Nagae, Hayato Tsurugi,* and Kazushi Mashima*
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
C-H activation, Aminoalkylation, diamine ligand, asymmetric reaction
ABSTRACT: A mixed ligated amidoyttrium complex, Y(NBn2)(L1)(THF)2 (8, L1 = N,N’-bis(2,6-diisopropylphenyl)ethylenedia-
mine), served as a catalyst for addition of the ortho-pyridyl C(sp2)—H bond of 2-substituted pyridines to non-activated imines; com-
plex 8 showed superior catalytic performance compared with Y[N(SiMe3)2]3 (1) and Y[N(SiMe3)2]2(NBn2)(THF) (2). Concerning
the reaction mechanism, we conducted a stoichiometric reaction of an alkylyttrium complex, Y(CH2SiMe3)(L1)(THF)2 (7), with 2-
ethylpyridine (4e), giving a mixture of (η3-pyridylmethyl)yttrium complex 9 and (η2-pyridyl)yttrium complex 10 along with elimina-
tion of SiMe4. Furthermore, addition of N-(tert-butyl)-2-methylpropan-1-imine (5i) to the mixture of 9 and 10 afforded (pyridylme-
thylamido)yttrium complex 11 as a single product, and the catalytic activity of 11 was comparable to that of complex 8. Kinetic
analysis of the aminoalkylation reaction in the presence/absence of HNBn2 revealed that the reaction rate in the presence of HNBn2
was four times faster than that without HNBn2 due to acceleration of the product-eliminating step from complex 11 by HNBn2 to
regenerate amidoyttrium complex 8 and the product. In addition, we determined that the catalytic reaction obeyed a first-order rate
dependence on the catalyst concentration, independent of the imine concentration, and a second–order rate dependence on the con-
centration of the pyridine substrate in the reaction system, both with and without HNBn2. An enantiomerically pure N,N’-diaryl-1,2-
diphenylethylenediamido ligand was applied for the C(sp2)—H aminoalkylation reaction in combination with Lu(CH2SiMe3)3(THF)2
to give chiral aminoalkylated products in moderate yield with good enantioselectivity.
Functionalized N-heteroaromatic compounds are among the
most important skeletons of bio-active molecules often used in
pharmaceuticals and agrochemicals.1 Although various syn-
thetic protocols to introduce any functional group in N-heteroar-
omatics have been intensively developed, metal catalyzed C—
H bond activation followed by functionalization is one of the
most atom-economical and cost-effective synthetic tools in
terms of excluding the pre-functionalization step of any sub-
strates and minimizing the formation of byproducts. In fact, the
insertion of non-polar C=C (alkene) and C≡C bonds (alkyne)
into a C—H bond of pyridine and its derivatives is catalyzed by
various transition metal complexes to give ortho-, meta-, and
para-substituted alkyl and alkenyl pyridine derivatives, respec-
tively.2-8 Typically, low-valent late-transition metal catalyst
systems such as nickel(0) complexes combined with Lewis acid
activators as well as [RhCl(coe)2]2 supported by PCy3 work in
alkylation and alkenylation reactions (Figure 1(a)), while alkyl
and hydride complexes of d0 lanthanide metals and early-tran-
sition metals serve as catalysts for ortho-alkylation through the
σ-bond metathesis pathway, in which 2-pyridine species are
key intermediates prior to insertion of the C=C bond (Figure
1(b)).9-11 Although insertion of non-polar unsaturated sub-
strates into a C—H bond of pyridine derivatives has been
widely demonstrated, the catalytic insertion of polar multiple
bonds,12 such as C=N,13a-d C≡N,13e and C=O,13f-h is still consid-
ered to be a difficult task, and only a few catalytic reactions
have been successfully established. Relevantly, Bergman and
Ellman reported that the electrophilic rhodium(III) system of
[Cp*RhCl2]2/AgSbF6 is a catalyst for the C—H bond activation
of the arene ring of 2-arylpyridines followed by insertion of
Boc-protected imines, leading to the selective aminoalkylation
at the arene ring of 2-arylpyridines,13a and Shi et al. reported
that a dicationic rhodium catalyst, [Cp*Rh(CH3CN)3][SbF6]2,
assists in the activation of the C—H bond of the aryl ring of 2-
phenylpyridine, followed by the addition to N-sulfonyl al-
dimines to give the corresponding N-sulfonyl arylmethyla-
mines.13b After these rhodium catalyst systems appeared, al-
kylcobalt and dicationic cobalt catalysts were also applied to the
same regioselective C—H aminoalkylation of 2-arylpyridines
with N-arylbenzaldimines and N-sulfonyl benzaldimies, respec-
tively.13c,d
Figure 1. (a) Late transition metal catalysts for alkylation and
alkenylation of pyridine derivatives; (b) Lanthanide and early
transition metal catalysts for ortho-selective alkylation of pyri-
dine derivatives.
In contrast to these successful insertion reactions of an acti-
vated C=N double bond and a C≡N triple bond, we recently
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found that homoleptic triamido complexes of group 3 metals
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and lanthanides, M[N(SiMe3)2]3, act as catalysts in the presence
of HNBn2 for selective insertion of non-activated imines into
the ortho-C—H bond of the pyridine ring of 2-arylpyridines.14
Noteworthy is that the achieved regioselectivity for C—H bond
functionalization of the ortho-C—H bond of the pyridine moi-
ety of 2-arylpyridines differed from the electrophilic late-tran-
sition metal catalyst systems that selectively aminomethylate at
the aryl ring of 2-arylpyridines, as schematically outlined in
Scheme 1. As part of our continuing interest, we herein report
that application of both chelating N,N’-diarylethylenediamido
ligands and HNBn2 onto yttrium complexes produces bidentate
ligand-supported catalysts for aminoalkylation of the ortho-C—
H bond of N-heteroaromatic compounds with non-activated
imines. Based on the results for screening the effective achiral
bidentate nitrogen-based ligand series, we achieved the first ex-
ample, to the best of our knowledge, for asymmetric C—H ami-
noalkylation of 2-phenylpyridine using a C2-symmetric
(1S,2S)-N,N’-dimesityl-1,2-diphenylethane-1,2-diamido-sup-
ported lutetium complex, although Cramer15 and Ellman16 re-
ported asymmetric C—H alkoxymethylation and aminomethyl-
ation of aromatic compounds catalyzed by rhodium complexes,
respectively. Moreover, the mechanism of this aminoalkylation
reaction was investigated based on isolation and characteriza-
tion of some key intermediates as well as kinetic study.
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We further checked the additive effects of secondary amines
on alkylyttrium complex 7, and the results are shown in Table
1. The yield of the aminoalkylated product 6aa was improved
to 92% yield when combined with HNBn2, whereas the addition
of HN(SiMe3)2 to 7 suppressed the yield of 6aa to 66% (entries
1—3), consistent with the experimental results that the in situ
mixture of 1 and L1, liberating HN(SiMe3)2, was inferior to that
of 3 and L1, releasing SiMe4. Bulkiness of the SiMe3 group on
the nitrogen atom on the yttrium species retarded the catalytic
reaction. Other secondary dialkylamines, such as HNCy2,
HN(iPr)(tBu), and HNnBu2, gave 6aa in good yields (83—85%,
entries 4—6). Consequently, we selected the combination of 7
and HNBn2, whose mixture quantitatively yielded the corre-
sponding five-coordinated complex 8 (eq. 2), as the best cata-
lyst system for the aminoalkylation reaction. In fact, isolated
complex 8 without the addition of HNBn2 exhibited almost the
same catalytic activity (94% yield) as that of the in situ mixture
of 7 and HNBn2 (entries 2 and 7).
Scheme 1. Different regioselectivity in metal-catalyzed C—H
bond aminoalkylation of 2-phenylpyridine with imines.
Table 1. Monodentate amine screening for ortho-C—H ami-
noalkylation reaction of 2-phenylpyridine.
Results and Discussion
We previously reported that a homoleptic tris(amido)yttrium
complex, Y[N(SiMe3)2]3 (1), and a mixed-ligated yttrium com-
plex, Y[N(SiMe3)2]2(NBn2)(THF) (2), can serve as first cata-
lysts for ortho C—H bond aminoalkylation of 2-substituted pyr-
idines with imines to give ortho-aminoalkylated compounds, in
which the mixed-ligated complex 2 has higher activity than
homoleptic complex 1.14 Hence, to further screen for mixed-
ligated tris(amido)yttrium complexes, we evaluated the cata-
lytic activity of a chelating system derived by treating
Y(CH2SiMe3)3(THF)2 (3) with 1 equiv of various chelating bi-
dentate diamines and tridentate-triamines, and found that N,N’-
bis(2,6-diisopropylphenyl)ethylenediamine (L1) was the best
chelating ligand to support the yttrium center among the other
bidentate and tridentate ligands we examined (see Supporting
Information). In fact, an in situ mixture of 3 and L1 exhibited
catalytic activity for the aminoalkylation of 2-phenylpyridine
(4a) with N,1-dicyclohexylmethanimine (5a) at 100 °C for 24 h
to give the aminoalkylated product 6aa in 79% yield. Catalytic
performance of this in situ mixture prompted us to isolate al-
kylyttrium complex 7 according to the procedure reported in the
literature (eq. 1),17 and the catalytic activity of 7 was found to
be the same as that observed for the in situ mixture of 3 and L1.
Entry
Additive
-
Yield (%)a
1
2
80
92
66
83
85
83
94
HNBn2
HN(SiMe3)2
HNCy2
HN(tBu)(iPr)
HNnBu2
-
3
4
5
6
7b
a Determined by 1H NMR with 1,1,2,2-tetrachloroethane as an internal
standard. b Isolated complex 8 was used.
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The substrate scope of imines was examined for the amino- Table 2. Scope and limitations of imine substrates.
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3
4
5
6
7
8
alkylation of 4a with various imines 5, and the results are sum-
marized in Table 2. Steric effects of substituents at the carbon
atom of N-cyclohexylimines were highly sensitive: N-cyclo-
hexyl-2,2-dimethylpropan-1-imine (5b) bearing a tertiary butyl
group at the imine carbon gave aminoalkylated product 6ab in
63% yield (entry 1). When secondary alkyl substituents such
as CHEt2 and isopropyl were introduced at the imine carbon,
the corresponding aminoalkylated compounds 6ac and 6ad
were obtained in moderate yields (57% yield for 6ac; 69% yield
for 6ad; entries 2 and 3), suggesting that no significant effect of
the bulkiness at the imine carbon substituent was observed for
the aminoalkylation reaction. In sharp contrast, reaction of 4a
with less hindered N-cyclohexylhexan-1-imine (5e) resulted in
a much lower yield of the aminoalkylated product 6ae (entry 4),
presumably due to the decomposition of the catalyst by prefer-
entially reacting the yttrium complex with 5e. In fact, complex
7 rapidly reacted with 5e to afford complicated mixture, from
which we could not characterize any yttrium species. The ami-
noalkylation reaction using N-cyclohexylbenzylideneimine (5f)
afforded 6af in 34% yield, even when using 20 mol% of 7 and
HNBn2 at 130 °C for a prolonged reaction time (72 h, entry 5).
It was likely assumed that the low reactivity of 5f was ascribed
to the low coordination ability of the imine nitrogen atom of 5f
to the yttrium center, while electron-rich imines 5a-d preferen-
tially coordinated to the metal center to promote the aminoal-
kylation reaction. The steric bulkiness of the nitrogen substitu-
ents also affected the product yield. In fact, no product was
observed for aminoalkylation using N-tert-butyl-2,2-dime-
thylpropan-1-imine (5g) (entry 6), whereas N-tert-butylimines
with cyclohexyl and isopropyl groups at the imine carbons, i.e.,
N-tert-butyl-1-cyclohexylmethanimine (5h) and N-(tert-butyl)-
2-methylpropan-1-imine (5i), were applicable to reach 70% and
80% yields, respectively (entries 7 and 8). Aminoalkylations
with N-isopropylimine, 1-cyclohexyl-N-isopropylmethanimine
(5j), occurred effectively to give 6aj in 76% yield (entry 9).
When a primary alkyl substituent bound to the imine nitrogen
atom, such as N-(n-hexyl)-1-cyclohexylmethanimine (5k), ami-
noalkylated product 6ak was obtained in only a trace amount
(entry 10), probably due to the low reactivity of the Y—N(pri-
mary alkyl) bond.
Entry
Imine
5b
5c
R1
Cy
R2
tBu
Product Yield (%)a
1
2
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
63
57b
69
9
Cy
CHEt2
iPr
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3
5d
5e
Cy
4
Cy
npentyl
<5
5
5f
Cy
Ph
34c
n.d.
70
6
5g
tBu
tBu
tBu
iPr
tBu
7
5h
5i
Cy
8
iPr
80
9
5j
5k
b
Cy
6aj
6ak
76
10
nhexyl
Cy
trace
Isolated yield. HNCy2 was used for 48 h. c 20 mol% catalyst and
HNCy2 was used at 130 °C for 72 h.
a
We further evaluated the substrate scope for the aminoal-
kylation reaction of N-heteroaromatic compounds with N,1-di-
cyclohexylmethanimine (5a), and the results are shown in Table
3. 2-Arylpyridines with electron-donating methoxy and methyl
substituents at the para-position of the phenyl ring afforded
aminoalkylated products 6ba and 6ca in 81% yield. In contrast,
aminoalkylated product 6da bearing a trifluoromethyl group at
the para-position of the phenyl ring was obtained in lower yield
(60%) compared with 6ba and 6ca. Under the same conditions,
3- and 4-phenylpyridines did not afford any corresponding
products, suggesting that the substituent at the 2-position was
indispensable for the aminoalkylation reaction. Pyridines with
2-ethyl, (4e), 2-isopropyl (4f), and 2-benzyl (4g) substituents
were converted to the corresponding aminoalkylated pyridines
6ea—ga in 66%, 60%, and 50% yield, respectively. 1-Phenyl-
isoquinoline (4h) reacted with 5a at the 3-position to produce
6ha in 81% yield, and the yield and regioselectivity were com-
parable to the aminoalkylation of 2-phenylpyridine. In contrast,
aminoalkylation of quinoline (4i) did not proceed smoothly and
product 6ia was obtained in only 34% yield; however, no other
regioisomers, such as aminoalkylation at the 8-position, were
detected. Aminoalkylation of 2-phenylthiazole (4j) occurred
exclusively at the 5-position to afford 6ja in 76% yield. As N-
methylbenzimidazole (4k) was one of the most suitable sub-
strates for C—H activation, treatment with 5a produced 6ka in
80% yield, and N-alkyl substituted imines such as 5k and 5l
having n-hexyl and benzyl substituents on the imine nitrogen
atom were also applicable to produce the corresponding amino-
alkylated products 6kk and 6kl in 69% and 82% yield. When
pyridine or 3- and 4-substituted pyridines were used as the sub-
strates, no aminoalkylated products were obtained as consistent
with the our previous observation of the dimerization of the pyr-
idine derivatives via ortho-C—H bond activation and C=N in-
sertion of the pyridine ring.10a,b,18
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Table 3. Scope and limitations of N-heteroaromatics.a
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Figure 2. Second-order plot on 2-phenylpyridine at five different
temperatures in the absence of HNBn2.
a Isolated yield. b HNCy2 was used for 24 h. c HNCy2 was used for 48 h.
Kinetic study of 7 in the absence of HNBn2
We measured the rate concentration dependences of 7, 2-phe-
nylpyridine (4a), and N,1-dicyclohexylmethanimine (5a) to cat-
alytically producing 6aa in the absence of HNBn2. We observed
a first–order rate dependence on the catalyst concentration of 7
over a 4-fold range, and the initial rate of the reaction was inde-
pendent of the concentration of 5a in the range of 0.30 M to
0.60 M. On the other hand, the reaction showed a second–order
rate dependence on the concentration of 4a. Overall, the rate
law obeyed [4a]2[5a]0[7], the same as in our previous kinetic
study of Y[N(SiMe3)2]2(NBn2)(THF) (2). Monitoring the reac-
tion progress allowed us to determine kobs using 1H NMR spec-
troscopy in the temperature range of 101 to 120 °C, and Eyring
analysis provided the following activation parameters: ∆H‡ =
50.0 ± 3.1 kJmol-1, ∆S‡ = -144.2 ± 8.0 JK-1mol-1, and ∆G‡(298
K) = 93.0 ± 5.5 kJmol-1 (Figures 2 and 3). The large negative
∆S‡ value suggested that an ordered five-coordinated intermedi-
ate involving two molecules of 4a might play a key role in the
C—H activation process.
Figure 3. Eyring plot for the aminolakylation reaction in the ab-
sence of HNBn2.
Catalytic cycle for 7 in the absence of HNBn2
Scheme 2 shows a plausible mechanism for the aminoalkylation
reaction of 2-substituted pyridines 4 with imines 5 catalyzed by
complex 7 in the absence of HNBn2. The initial step is a σ-bond
metathesis of 7 with 4 to produce a five-coordinated η2-pyridyl
species A, which was confirmed by the controlled experiment
of 7 and 2-ethylpyridine (vide infra). Further reaction of the
Y—C(sp2) bond in A with 5 generates species B containing
five-membered 2,5-diazametallacyclopentane with coordina-
tion of THF, which was observed during the catalytic reaction
and isolated in a stoichiometric reaction (vide infra). Ligand
exchange of the THF to 4 as well as dissociation of the chelating
pyridine ring with coordination of second molecule of 4 pro-
duce five-coordinated amidoyttrium species C. Subsequent
C—H bond activation by the Y—N bond is expected to be the
rate-determining step. Aminoalkylated product 6 is finally
eliminated along with regeneration of the catalytically active
species A with coordination of THF. Coordination of two mol-
ecules of 4 to the metal center in the rate-determining step is
supported by the second-order rate dependence of 4 in the cata-
lytic reaction. Observation of species B during the catalytic re-
action is likely ascribed to the equilibrium between species A
and B, in which species A with a five-membered chelation is
assumed to be a major species in the equilibrium. In addition,
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at a later stage of the catalytic reaction, a reverse reaction of the
Treatment of the in situ-generated mixture of 9 and 10 with
protonation of (η2-pyridyl)yttrium A by 6 was in equilibrium.
imine 5i in benzene at room temperature for 12 h afforded five-
membered chelate complex 11 as a single product in 85% yield
1
2
3
4
5
6
7
8
1
(eq. 4). In the H NMR spectrum of 11, signals assignable to
Scheme 2. A reaction mechanism for the aminoalkylation re-
action in the absence of HNBn2.
the methylene protons of the ethyl group bound to the pyridine
ring were separately observed as broad multiplets at δ 2.03 and
1.88, and one broad triplet signal with 3H intensity assignable
to the methyl group of the ethyl moiety was detected at δ 0.63
(3JHH = 8.0 Hz), in accordance with the selective insertion of 5i
into the Y—C(sp2) bond in complex 10, even though a mixture
of 9 and 10 was generated. Overall, the structure of 11 was
revealed by X-ray analysis as shown in Figure 4. The selective
formation of 11 indicated that major complex 9 was isomerized
into the more reactive complex 10 in the presence of 5i, though
the details of the isomerization mechanism between 9 and 10
are not clear; similar isomerization of cyclometallated yttrium
complexes into the corresponding (η2-pyridyl)yttrium com-
plexes was reported by Jordon21a and Diaconescu.21b A notable
9
10
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1
observation was that complex 11 was detected upon H NMR
spectroscopy monitoring of the catalytic reaction mixture of 4e
and 5i in the presence of 10 mol% of 7 at 100 °C after 30 min,
clearly revealing that complex 11 was a key reaction intermedi-
ate corresponding to B in Scheme 2 (vide supra). Inversely,
quantitative formation of complex 11 was also achieved upon
reacting the mixture of 9 and 10 with the isolated aminoalkyl-
ated product 6ei via protonation of the yttrium—carbon bonds
of 9 and 10 (eq. 5). Finally, we confirmed that the five-mem-
bered chelate complex 11, corresponding to B in the catalytic
cycle, served as an effective catalyst for the aminoalkylation re-
action of 4e and 5i to give the corresponding product 6ei in 85%
yield after 24 h under optimized reaction conditions (eq. 6).
Aiming to elucidate the mechanism, we performed some
control experiments. We conducted the reaction of complex 7
with 2-ethylpyridine (4e) to give a mixture of (η3-pyridylme-
thyl)yttrium complex 9 and (η2-pyridyl)yttrium complex 10 in
a 7:1 ratio (eq. 3). We previously reported the C—H bond ac-
tivation of 2-arylpyridines by 7, producing dianionic 2,2’-bi-
pyridyl-bridged dinuclear yttrium complexes.19 In the 1H NMR
spectrum of the major product 9, we observed a doublet signal
assignable to the methyl group at δ 1.44 (3JHH = 5.2 Hz). In
addition, four signals were detected due to the pyridine ring at
 6.15 (3-py), 6.63 (4-py), 5.63 (5-py), and 7.67 (6-py), indicat-
ing that C(sp3)—H bond activation at the α-position of the ethyl
group occurred in complex 9. The 13C NMR spectrum dis-
played one doublet signal for the methylene carbon bound to
yttrium at δ 62.8 (1JYC = 2.1 Hz). The coupling constant with
yttrium was smaller than that observed for normal carbons at-
tached to yttrium with
a
sp3-configuration, such as
Cp*2YCH(SiMe3)2 (1JYC = 36.6 Hz) and 7 (1JYC = 45.3 Hz),
whereas it was comparable to the terminal carbons of the 3-
allyl moiety observed for Cp*2Y(η3-C3H5) (1JYC = 3.8 Hz), in-
dicating that the C(sp3)—H activated 2-ethylpyridine moiety in
complex 9 coordinated to the metal center as a η3-aza-allyl
structure.20
A single crystal of complex 11 suitable for X-ray crystallo-
graphic analysis was obtained from a saturated hexane solution
of complex 11 at -40 °C. The molecular structure of 11 is
shown in Figure 4. The yttrium atom is surrounded by the N1
and N2 atoms of L1, the N3 atom of the amido group, the N4
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Page 6 of 13
atom of the pyridyl group, and one THF molecule to adopt a the catalyst compared with the reaction in the absence of HNBn2,
1
2
3
4
5
6
7
8
distorted five-coordinated square pyramidal geometry where
N1—N4 occupies the square plane and O1 occupies the axial
position. The bond lengths of Y1—N1 (2.216(3) Å), Y1—N2
(2.279(3) Å), and Y1—N4 (2.239(4) Å) are similar to the Y—
and in the range of 1.5—2.5 equiv, the reaction rate was almost
the same.
N
bonds in four-coordinated Y(L1)[N(SiMe3)2](THF)
(2.191(10), 2.213(11), and 2.261(13) Å, respectively)22 and re-
lated five-coordinated yttrium complexes containing amido lig-
ands (2.25—2.35 Å).22 The bond length of Y1—N3 (2.586(11)
Å) is within the range of other Y—N(pyridine) bonds (2.48—
2.62 Å).20a,23
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Second-order plot on 2-phenylpyridine at five differ-
ent temperatures in the presence of HNBn2.
Figure 4. Molecular structure of 11 with 30% thermal ellipsoids.
Isopropyl groups on L1 and all hydrogens are omitted for clarity.
Selected distances (Å) and angles (deg): Y1—N1 = 2.216(3), Y1—
N2 = 2.279(3), Y1—N3 = 2.586(11), Y1—N4 = 2.239(4), Y1—O1
= 2.384(3), N1—Y1—N2 = 80.74(11), N3—Y1—N4 = 69.32(13),
N4—Y1—O1 = 107.20(14), N3—Y1—O1 = 83.98(12), N2—
Y1—O1 = 102.78(12), N1—Y1—O1 = 102.01(11).
Figure 6. Eyring plot for the aminoalkylation reaction in the
presence of HNBn2.
Kinetic study of 7 in the presence of HNBn2
We checked for additive effects of HNBn2 on the reaction rate
using the same amounts of 7 and HNBn2. HNBn2 increased the
overall reaction rate. The reaction rate had a first–order rate
dependence on 7/HNBn2 concentration, was independent of the
imine concentration, and had a second–order rate dependence
on the 4a concentration, which was similar to the catalytic re-
action in the absence of HNBn2. Eyring analysis of the catalytic
reaction provided the following activation parameters, ∆H‡ =
36.5 ± 1.2 kJmol-1, ∆S‡ = -166.9 ± 3.1 JK-1mol-1, and ∆G‡(298
K) = 86.3 ± 2.1 kJmol-1. Furthermore, a deuterium-labeling ex-
periment using 2-phenylpyridine-d9 afforded a kinetic isotope
effect value of 2.65, indicating that C—H bond activation was
the rate-determining step, similar to the catalytic system of 2.
Thus, the large negative ∆S‡ value suggested a highly ordered
transition state for the C—H bond activation step via σ-bond
metathesis between a Y—N bond in five-coordinated amido yt-
trium species 8’ where two of the THF molecules in 8 were re-
placed by substrates or solvent, as shown in Scheme 3 (vide in-
fra), and a C—H bond of pyridines 4.14
Catalytic cycle of 7 in the presence of HNBn2
Scheme 3 shows a plausible reaction mechanism for the amino-
alkylation reaction of pyridine derivatives 4 with imines 5 cat-
alyzed by complex 7 in the presence of HNBn2, giving the cou-
pling products 6. The initial step is the spontaneous reaction of
7 with HNBn2 to give (dibenzylamido)yttrium complex 8’ with
coordination of two molecules of 4, similar to the bis(THF) ad-
duct 8 in eq 2. In fact, the decreased effectiveness of
HN(SiMe3)2 as the additive in the catalytic reaction, as shown
in Table 1, was consistent with the formation of isolable four-
coordinated amidoyttrium complex Y(L1)[N(SiMe3)2](THF),
in which the coordination sphere around the yttrium is very
crowded.22 A σ-bond metathesis reaction between Y—N bond
in 8’ and ortho C—H bond of 4 occurs to afford η2-pyridyl spe-
cies A. Second-order rate dependence on the concentration of
4 and KIE value suggest that this C—H bond activation is the
rate-determining step during the catalytic cycle. Insertion of
imine 5 into to the Y—C(sp2) bond of A is a C—C bond form-
ing step to generate imine-inserted species B, which is a similar
step to the catalytic reaction without HNBn2, as shown in
Scheme 2. Product 6 was eliminated by protonation of B by
HNBn2 to preferentially generate 8’, which is interconvertible
The additive effects of HNBn2 on the initial reaction rate
were further investigated over the range of 0—2.5 equiv to the
alkylyttrium complex 7. The overall reaction was accelerated
by increasing the amounts of HNBn2 up to 1.5 equiv added to
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We further examined the reaction of 8 and aminoalkylated
to B by protonation by product 6 (vide infra). Kinetic analysis
1
2
3
4
5
6
7
8
of the aminoalkylation reaction in the presence/absence of
HNBn2 revealed that the reaction rate (kobs) in the presence of
HNBn2 was four times faster than that without HNBn2. The
observed additive effects of HNBn2 in the range of 1.0 to 1.5
equiv indicated that HNBn2 worked as a free secondary amine
to increase the reaction rate by protonation of species B in
Scheme 3 to regenerate the amidoyttrium 8’ and the product. In
addition, facile formation of 8’ from species B is an additional
factor for enhancing the catalytic activity due to the no necessity
for dissociating the chelating pyridine ring in species B.
product 6ei in C6D6/THF at room temperature and monitored
the reaction by NMR spectroscopy, where THF was used as the
coordinating molecule to simplify the characterization of the yt-
trium species. In the reaction mixture, we found signals due to
both of complexes 8 and 11 in a 5:1 ratio in the reaction mixture
at room temperature (eq. 8), suggesting that complexes 8 and
11 were in equilibrium and complex 8 preferably formed in the
catalytic reaction, even in the presence of 6ei. A van’t Hoff
analysis on the 1:1 mixture of complex 8 and 6ei gave a linear
slope between 304-346 K with the values of ∆HΘ = 36.8 ± 2.7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
kJmol-1, ∆SΘ = 93.4 ± 8.3 JK-1mol-1, ∆GΘ (298 K) = 9.02 ±
0.21 kJmol-1. The positive standard Gibbs free energy also con-
sistent with the favored formation of complex 8 in the presence
of 6ei. This amido exchange reaction to release the reaction
product was similar to the product elimination step in the lan-
thanide-catalyzed hydroamination.24
Scheme 3. A reaction mechanism for the aminoalkylation re-
action in the presence of HNBn2.
Asymmetric C—H aminoalkylation
It is a challenging task to accomplish the asymmetric aminoal-
kylation reaction via C—H bond activation of pyridine deriva-
tives.16 We thus focused our attention on the usage of chiral
diamines with an ethylene skeleton and a binaphthyl-based
skeleton25 for Y(CH2SiMe3)3(THF)2 (3), and the results are
shown in Table 5. The enantioselective aminoalkylation reac-
tion of 4a with 5a using a catalyst system of 3 (10 mol%),
(1S,2S)-N,N’-dimesityl-1,2-diphenylethane-1,2-diamine (L9)
(10 mol%), and HNBn2 (10 mol%) under optimized conditions
(100 °C, 48 h) gave 6aa in 57% yield with 65% ee (entry 1).
When 2,6-diisopropylphenyl group was introduced on the nitro-
gen atom, the catalytic activity was decreased to 14% yield and
no chiral induction was observed (entry 2), though the N-aryl
substituent was similar to the best ligand to the non-chiral sys-
tem. Removal of substituents at the 2,6-positions resulted in a
significantly lower yield (entry 3). The use of (1S,2S)-N,N’-
bis(2-methoxyphenyl)-1,2-diphenylethane-1,2-diamine (L12)
improved enantioselectivity up to 97%, although the catalytic
activity was much lower (20% yield, entry 4), while introducing
two methoxy groups at the ortho positions of the aryl rings in
L13 did not afford the product in good yield (entry 5). Ligands
L14 and L15 with less bulky substituents than L9 produced the
aminoalkylated product with low yield and low enantioselectiv-
ity (entries 6 and 7). The cyclohexane backbone in L16 de-
creased not only the catalytic activity but also the enantioselec-
tivity of the product compared with the L9 system, while
binaphthyldiamine-based ligand L17 exhibited no catalytic ac-
tivity (entries 8 and 9). Enantioselectivity increased as the re-
action temperature decreased for the L9 system, 75% ee at
80 °C and 82% ee at 60 °C (entries 10 and 11). Accordingly,
we selected L9 as the best chiral diamine ligand.
When a mixture of 7, HNBn2, 4e, and 5i in C6D6 was mon-
itored by 1H NMR spectroscopy, we observed signals due to 11
corresponding to species B, but no signals were detected assign-
able to the C—H bond activated complexes 9 and 10 corre-
sponding to species A, probably due to the rapid insertion of
imine 5i to A to form diazametallacycle B as well as rapid pro-
tonation of the Y—C bond of species A by in situ generated
HNBn2. In fact, the mixture of complexes 9 and 10, in situ gen-
erated from 7 and 4e, was immediately protonated by HNBn2 to
give complex 8 with the release of 4e (eq. 7).
We checked the effect of the metal center for the enantiose-
lective aminoalkylation reaction. When Sc(CH2SiMe3)3(THF)2
was used instead of 3 under the same reaction conditions using
L9, 6aa was obtained in 14% yield and 65% ee (entry 12). In
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contrast, an in situ catalyst system of Lu(CH2SiMe3)3(THF)2
Page 8 of 13
1
Complex 12 was characterized by H and 13C NMR spec-
troscopy together with X-ray crystallographic analysis. The 1H
NMR of 12 in C6D6 displayed two sets of broad doublet signals
at δ 0.09 and -0.36 (2JHH = 11.2 Hz) assignable to diastereotopic
methylene protons of LuCH2SiMe3 along with aromatic protons
(δ 7.27—6.69) and methine protons (δ 5.69). The integral ratio
1
2
3
4
5
6
7
8
and L9 showed good catalytic behavior to give the product in
57% yield with 78% ee (entry 13). The superiority of the lute-
tium complex was attributed to the low solubility of the lutetium
complex 12 for removing the impurity; in fact, we isolated 12
in 42% yield by treating Lu(CH2SiMe3)3(THF)2 with an
equimolar amount of L9 in C6H6 at room temperature for 6 h
(eq. 9) and subsequent recrystallization gave the light yellow
microcrystalline solid, whereas the same reactions of trialkyl
complexes of scandium and yttrium with L9 resulted in the for-
mation of semi-solids that contained unidentified byproducts.26
1
in the H NMR confirmed coordination of the two THF mole-
cules to the lutetium center. In addition, a single crystal of com-
plex 12 suitable for X-ray crystallographic analysis was ob-
tained from a saturated hexane solution of complex 12 at -40 °C,
and the molecular structure of 12 is shown in Figure 7. The
lutetium atom is surrounded by the N1 and N2 atoms of the
(1S,2S)-N,N’-dimesityl-1,2-diphenylethane-1,2-diamido ligand,
O1 and O2 atom of THF molecules, and C5 atom of the neosilyl
group, to adopt a distorted square pyramidal geometry where
N1, N2, O1, and O2 occupies the basal plane and C5 occupies
the axial position. The bond lengths of Lu1—N1 (2.193(3) Å),
Lu1—N2 (2.176(3) Å) are similar to the Lu—N bonds in related
five-coordinated lutetium alkyl complex with a ferrocenyldi-
amido ligand (range 2.18—2.24 Å).17 The Lu—O bonds are in
the range of 2.33—2.35 Å observed in related penta-coordi-
nated Lu alkyl complexes.17,27 The angles of Lu1—N1—C1
and Lu1—N2—C4 (127.5(2)° and (125.4(2)°) are smaller than
those observed in group 3 metal alkyl complexes bearing eth-
ylenediamine ligands.17
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Enantioselective aminoalkylation of 4a.
Entry
Ligand
M
Temp. (°C)
Yield (%)a
ee (%)b
1
2
L9
L10
L11
L12
L13
L14
L15
L16
L17
L9
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Sc
Lu
100
100
100
100
100
100
100
100
100
80
57
14
9
65
racemic
n.d.
97
3
4
20
<5
16
21
32
<1
55
41
14
57
5
n.d.
27
6
7
5
8
29
9
n.d.
75
10
11
12c
Figure 7. Molecular structure of 12 with 30% thermal ellipsoids.
All hydrogens are omitted for clarity. Selected distances (Å)
and angles (deg): Lu1—N1 = 2.193(3), Lu1—N2 = 2.176(3),
Lu1—O1 = 2.336(3), Lu1—O2 = 2.302(3), Lu1—N1—C1 =
L9
60
82
L9
80
65
13d
L9
80
78
127.5(2), Lu1—N2—C4
77.56(11).
= 125.4(2), N1—Lu1—N2 =
a
Determined by 1H NMR with 1,1,2,2-tetrachloroethane as an internal
standard. b Determined by HPLC analysis. c Sc(CH2SiMe3)3(THF)2 was
used instead of 3. d Lu(CH2SiMe3)3(THF)2 was used instead of 3.
Similar to the formation of amidoyttrium complex 8, an al-
kyllutetium moiety reacted with HNBn2 at room temperature to
1
afford the corresponding amide complex 13 (eq. 10). The H
NMR of 13 displayed two doublet signals at  4.57 and 4.47
(2JHH = 13.6 Hz) due to diastereotopic benzylic protons of
NCH2Ph. The integral ratio in the 1H NMR confirmed coordi-
nation of the two THF molecules to the lutetium center, forming
the five-coordinated amidolutetium complex.
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the corresponding chiral products with moderate to good enan-
1
2
3
4
5
6
7
8
tiomeric excess.
Experimental section
General
All manipulations involving air- and moisture-sensitive organ-
ometallic compounds were carried out under argon using the
standard Schlenk technique or argon-filled glovebox. Organo-
metallic reagents, LiCH2SiMe3 and M(CH2SiMe3)3(THF)2 (M =
Y, Sc, Lu), and achiral chelating diamines ligands L1—L8 were
prepared according to the literatures.22,28,29 The chiral diamine
ligands L9—L17 were prepared according to the literatures us-
ing Buchwald-Hartwig C—N cross coupling recation.30 Al-
kylyttrium complex 7 was synthesized in similar manner to the
literature.17 Amines and aldehydes for synthesizing imines and
chiral diamines for synthesizing L9—L17 were purchased and
used as received. N-heteroaromatics and secondary amines
were purchased and purified by distillation over CaH2. Hexane,
pentane, toluene, and benzene-d6 were distilled over CaH2 and
thoroughly degassed by trap-to-trap distillation before use.
NMR spectra were recorded on a Bruker AV 400M spectrome-
ter in 5 mm NMR tube. Chemical shifts were reported in parts
per million and referenced to residual proton signal of the sol-
vent (1H benzene-d6, = 7.15; chloroform,  = 7.26) or the sol-
vent itself (13C{1H} benzene-d6,  = 128.06; chloroform,  =
77.16). HPLC spectra were recorded on a JASCO UV-2075
and PU-2089. Optical rotation values were recorded on a
JASCO DIP-370 polarimeter at 589 nm (sodium lamp) and
given in 10-1 deg cm2 g-1. Melting points were recorded by a
BUCHI Melting Point M-565. The elemental analyses were
recorded by using Perkin Elmer 2400 at the Faculty of Engi-
neering Science, Osaka University. Flash column chromatog-
raphy was performed using silica gel 60 (0.040–0.063 mm,
230–400 mesh ASTM).
The isolated chiral lutetium complex 13 was used as a cata-
lyst for the aminoalkylation reaction of 2-arylpyridines 4a—d
having different substituents at the para-position of the aryl ring,
and the results are summarized in Table 5. Chiral aminoalkyl-
ated product 6aa was obtained in 60% yield with 84% ee at
80 °C for 48 h. Methoxy-substituted substrate 4b was less ef-
fective for the catalytic reaction, whereas the enantioselectivity
was almost the same. When electron-donating methyl group
was introduced at the para-position of the phenyl group, the
yield of 6ca was similar, whereas the enantioselectivity de-
creased to 69%. By introducing an electron-withdrawing sub-
stituent, the yield of 6da decreased to 24%, while the enantiose-
lectivity was the same as that of 6aa.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Enantioselective aminoalkylation reaction of 2-ar-
ylpyridine 4a—d.
Preparation of (L1)YNBn2(THF)2 (8)
Complex 7 (80.0 mg, 0.114 mmol) dissolved in 2 mL of toluene
was dropwise added to a solution of dibenzylamine (22.5 mg,
0.114 mmol) in 2 mL toluene at room temperature. The reac-
tion solution was stirred for 2 h at room temperature and
changes color from yellow to orange, and then all volatiles were
evaporated. The resulting oily compound was washed with
pentane. After drying the solid under reduced pressure, 8 was
isolated as light orange powder in 54% yield (50.0 mg, 61.8
μmol), mp 130-132 °C (dec). 1H NMR (400 MHz, C6D6,
a Isolated yield. b Determined by HPCL analysis. c HNCy2 was used.
Conclusion
3
30 °C): δ 7.41(d, JHH = 5.6 Hz, 4H, o-Ph), 7.32-7.17 (m, 7H,
We demonstrated that a mixed ligated amidoyttrium complex 8
supported by a N,N’-diarylethylenediamido ligand and a diben-
zylamido ligand exhibited sufficient catalytic activity for ami-
noalkylation reaction of 2-substituted pyridine derivatives
through insertion of a non-activated C=N bond of imines into
an ortho-C(sp2)—H bond. Control experiments to isolate some
intermediate species and measure the kinetics revealed plausi-
ble reaction mechanisms, leading us to propose a five-coordi-
nated species as a key intermediate before the C—H bond
breaks through a highly ordered σ-bond metathesis transition
state, and additive amine HNBn2 worked to accelerate the for-
mation of product 6 and the regeneration of 8 as shown in
Scheme 3. Because 8 involved a five-membered chelating lig-
and, we introduced (1S,2S)-N,N’-dimesityl-1,2-diphe-
nylethane-1,2-diamine (L9) as a chiral diamine to a trial-
kyllutetium complex Lu(CH2SiMe3)3(THF)2 for a chiral C—H
aminoalkylation reaction of 2-arylpyridine derivatives to gain
Ar + Ph), 7.17-7.04 (m, 5H, Ar + Ph), 4.37 (s, 4H, NCH2), 4.25
3
(sept, JHH = 6.4 Hz, 4H, CH(CH3)2), 4.11 (s, 4H, NCH2Ph),
3
3.34 (br s, 8H, α-CH2 of THF), 1.38 (d, JHH = 6.4 Hz, 24H,
CH(CH3)2)1.01 (br s, 8H, β-CH2 of THF). 13C{1H} NMR (100
MHz, C6D6, 30 °C): δ 156.0, 145.7, 144.5, 128.6, 128.5, 126.3,
123.5, 122.0 (Ar and Ph), 70.3 (α-CH2 of THF), 60.2 (NCH2),
54.9 (NCH2Ph), 28.3 (CH(CH3)2), 26.0 (β-CH2 of THF), 25.0
(CH(CH3)2). Anal. Calcd for C48H68N3O2Y: C, 71.35; H, 8.48;
N, 5.20. Found: C, 71.07; H, 8.76; N, 5.71. Small deviation of
the E.A. values is due to high sensitivity of 8 to air.
Reaction of 7 with 2-ethylpyridine
To a solution of 7 (132.0 mg, 0.188 mmol) in benzene was
added a solution of 2-ethylpyridine (4e, 20.0 mg, 0.188 mmol)
in benzene at room temperature. The reaction mixture was
stirred for 12 h at room temperature and the reaction mixture
color changed from orange to brown, then it was filtered and
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Page 10 of 13
volatiles were removed under vacuum to obtain a brown solid the solid in vacuo for 3 h, 12 was isolated as light yellow pow-
1
2
3
4
5
6
7
8
as a mixture of 9 and 10 in 1:7 ratio, mp 75-77 °C (dec). For
10: 1H NMR (400 MHz, C6D6, 30 °C): δ 7.67 (d, 3JHH = 7.2 Hz,
1H, H of C6 2-Etpy), 7.23 (d, 3JHH = 7.6 Hz, 4H, m-Ar), 7.11 (t,
3JHH = 7.6 Hz, 2H, p-Ar), 6.62 (t, 3JHH = 7.6 Hz, 1H, H of C4 2-
Etpy), 6.16 (d, 3JHH = 8.4 Hz, 1H, H of C3 2-Etpy), 5.63 (t, 3JHH
der in 42% yield (92.0 mg, 0.108 mmol), mp 128-130 °C (dec).
1H NMR (400 MHz, C6D6, 30 °C): δ 7.25 (d, 3JHH = 5.6 Hz, 4H,
o-Ph), 6.91 (t, 3JHH = 7.2 Hz, 4H, m-Ph), 6.77 (t, 3JHH = 6.8 Hz,
2H, p-Ph), 6.69 (s, 4H, m-Ar), 5.68 (s, 2H, NCHPh), 3.34 (br s,
4H, α-CH2 of THF), 3.15 (br s, 4H, α-CH2 of THF), 2.69 (s,
12H, o-CH3 of Ar), 2.08 (s, 6H, p-CH3 of Ar), 0.91-1.14 (br m,
3
= 6.0 Hz, 1H, H of C5 2-Etpy), 4.15 (sept, JHH = 6.4 Hz, 4H,
2
CH(CH3)2), 4.04 (s, 4H, NCH2), 3.37 (br s, 8H, α-CH2 of THF),
2.58 (br s, 1H, YCHCH3), 1.45 (d, 3JHH = 5.2 Hz, 3H, YCHCH3),
1.40 (d, 3JHH = 6.4 Hz, 24H, CH(CH3)2), 1.05 (br s, 8H, β-CH2
of THF). 13C{1H} NMR (100 MHz, C6D6, 30 °C): δ 161.6 (C2
of 2-Etpy), 156.4 (i-Ar), 146.7 (C6 of 2-Etpy), 145.0 (o-Ar),
134.6 (C4 of 2-Etpy), 123.4 (m-Ar), 122.2 (p-Ar), 113.1 (C3 of
2-Etpy), 102.9 (C5 of 2-Etpy), 70.3 (α-CH2 of THF), 62.8 (d,
1JYC = 2.1 Hz, YCHCH3), 61.0 (NCH2), 28.3 (CH(CH3)2), 25.9
(β-CH2 of THF), 25.1 (CH(CH3)2).
8H, β-CH2 of THF), 0.37 (s, 9H, SiMe3), 0.09 (d, JHH = 11.2
2
Hz, 1H, LuCHH), -0.36 (d, JHH = 11.2 Hz, 1H, LuCHH).
13C{1H} NMR (100 MHz, C6D6, 30 °C): δ 152.4, 146.3, 132.7,
129.4 (m-Ar + o-Ph), 127.6, 126.9 (m-Ph), 125.7 (p-Ph), 77.9
(NCHPh), 69.8 (α-CH2 of THF), 34.8 (LuCH2), 24.9 (CH3),
22.3 (CH3), 20.8 (CH3), 5.0 (SiMe3). Anal. Calcd for
C44H61N2O2SiLu: C, 61.95; H, 7.21; N, 3.28. Found: C, 60.05;
H, 6.82; N, 3.86. Small deviation of the E.A. values is due to
high sensitivity of 12 to air.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
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44
45
46
47
48
49
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53
54
55
56
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Preparation of (L1)[N-{2-methyl-1-(6-ethylpyridine-2-
yl)propyl}tert-butylamido]Y(THF) (11)
Preparation of (L9)LuNBn2(THF)2 (13)
Complex 9 (104 mg, 0.122 mmol) dissolved in 2 mL of benzene
was dropwise added to a solution of dibenzylamine (24.1 mg,
0.122 mmol) in 2 mL benzene at room temperature. The reac-
tion solution was stirred for 2 h at room temperature. The color
of reaction mixture was changed from yellow to orange, and
then all volatiles were evaporated. The resulting oily compound
was washed with pentane. After drying the solid in vacuo for 3
h, 13 was isolated as light orange powder in 55% yield (65.0
mg, 67.0 μmol), mp 113-115 °C (dec). 1H NMR (400 MHz,
C6D6, 30 °C): δ 7.42-7.32 (br m, 3H, Ph), 7.31-7.18 (m, 6H, Ph),
7.13-7.06 (m, 2H, Ph), 6.97-6.84 (m, 4H, Ph), 6.84-6.61 (m, 8H,
To a solution of 7 (300 mg, 0.429 mmol) in benzene was added
a solution of 2-ethylpyridine (4e, 46.0 mg, 0.429 mmol) in ben-
zene at room temperature. The reaction mixture was stirred for
12 h at room temperature. N-(t-butyl)-2-methylpropan-1-imine
(5i, 55.0 mg, 0.429 mmol) was added to the reaction mixture
and stirred again at room temperature for 12 h. The reaction
solution was filtered and volatiles were removed under vacuum
to obtain a brown solid, which was washed with hexane (2 mL
×2). After drying the remaining solid in vacuo, 11 was isolated
as brown powder in 85% yield (292 mg, 0.364 mmol), mp 73-
75 °C (dec). 1H NMR (400 MHz, C6D6 + 5 equiv of THF-d8,
30 °C): δ 7.17 (m, 4H, m-Ar), 7.04 (br t, 3JHH = 7.2 Hz, 2H, p-
Ar), 6.91 (br t, 3JHH = 6.8 Hz, 1H, H of C4 2-Etpy), 6.53 (br d,
3JHH = 6.8 Hz, 1H, H of C3 or C5 2-Etpy), 6.36 (br d, 3JHH = 6.8
2
Ph + Ar), 5.70 (s, 2H, NCHPh), 4.56 (d, JHH = 13.6 Hz , 2H,
NCHHPh), 4.46 (d, 2JHH = 14.4 Hz , 2H, NCHHPh), 3.37 (br s,
4H, α-CH2 of THF), 3.29 (br s, 4H, α-CH2 of THF), 2.70 (s,
12H, o-CH3 of Ar), 2.10 (s, 6H, p-CH3 of Ar), 1.03 (br m, 8H,
β-CH2 of THF). 13C{1H} NMR (100 MHz, C6D6, 30 °C): δ
152.2, 146.2, 144.2, 132.8. 129.6, 129.3, 129.0, 128.7, 128.6,
126.9, 126.6, 125.7, 77.7 (NCHPh), 70.7 (α-CH2 of THF), 55.9
(NCH2Ph), 25.0 (, β-CH2 of THF), 22.2 (CH3), 20.8 (CH3). Anal.
Calcd for C54H64N3O2Lu: C, 67.41; H, 6.71; N, 4.37. Found: C,
66.79; H, 6.88; N, 4.71. Small deviation of the E.A values is
due to high sensitivity of 13 to air.
3
Hz, 1H, H of C3 or C5 2-Etpy), 4.46 (br d, JHH = 6.8 Hz, 2H,
NCHH), 4.13 (br s, 4H, CH(CH3)2 of Ar), 3.66 (br d, 3JHH = 6.8
Hz, 2H, NCHH), 3.53 (br s, 4H, α-CH2 of THF), 3.21 (br s, 1H,
NCH{CH(CH3)(CH3)}), 2.08-1.96 (br m, 1H, 6-CHHCH3 of 2-
Etpy), 1.96-1.81 (br m, 1H, 6-CHHCH3 of 2-Etpy), 1.43-1.28
(br m, 42H, NCH{CH(CH3)(CH3)}, NCH{CH(CH3)(CH3)},
YNC(CH3)3, CH(CH3)2 of Ar, and β-CH2 of THF), 0.63 (br t,
3JHH = 8.0 Hz, 3H, 6-CHHCH3 of 2-Etpy), 0.44 (br s, 3H,
NCH{CH(CH3)(CH3)}). 13C{1H} NMR (100 MHz, C6D6 + 5
equiv of THF-d8, 30 °C): δ 174.9, 163.9 (C2 and C6 of 2-Etpy),
157.4 (i-Ar), 144.7 (o-Ar), 137.8 (C4 of 2-Etpy), 123.7 (m-Ar),
121.1 (p-Ar), 119.6 (C3 or C5 of 2-Etpy), 118.6 (C5 or C3 of 2-
Etpy), 70.0 (NCH{CH(CH3)(CH3)}), 68.2 (α-CH2 of THF),
Reaction profile for the catalytic aminoalkylation reaction.
In a glovebox under argon, catalyst 7 (6.9 mg, 10 μmol), HNBn2
(1.9 L, 10 μmol), 2-phenypyridine (4a, 15.5 mg, 0.100 mmol),
imine 5a (38.7 mg, 0.200 mmol), phenanthrene (8.9 mg, 50
μmol) and C6D6 (0.5 mL) were added to a J-young capped NMR
tube. The NMR tube was heated in a 100 °C oil bath. The rates
59.7
(NCHH),
56.1
(YNC(CH3)3),
40.6
1
of the reactions were monitored by H NMR spectroscopy.
(NCH{CH(CH3)(CH3)}), 32.1 (YNC(CH3)3), 31.1 (6-CHHCH3
of 2-Etpy), 28.2 (CH(CH3)2 of Ar), 25.7 ((CH(CH3)2 of Ar) and
β-CH2 of THF), 22.5 (NCH{CH(CH3)(CH3)}), 21.7
(NCH{CH(CH3)(CH3)}), 12.6 (6-CHHCH3 of 2-Etpy). Anal.
Calcd for C45H71N4OY: C, 69.92; H, 9.26; N, 7.25. Found: C,
69.24; H, 9.16; N, 7.10. Small deviation of the E.A values is
due to high sensitivity of 11 to air.
1
Yield of product 6aa was determined by the integration of H
NMR signals of phenanthrene and CyNCH(Ar)Cy.
Kinetic analysis of the catalytic aminoalkylation reaction in
the presence of HNBn2.
In a glove box under argon, catalyst 7 (0.020—0.080 M), 2-
phenylpyridine (4a, 15.5 mg, 0.100 mmol), imine 5a (0.30—
0.60 M), phenanthrene (8.9 mg, 50 μmol), and toluene-d8 (0.5
mL) were added to a J-young capped NMR tube with/without
HNBn2. The NMR tube was heated at 90—110 °C using oil
Preparation of (L9)LuCH2SiMe3(THF)2 (12)
Lu(CH2SiMe3)3(THF)2 (150 mg, 0.258 mmol) dissolved in 10
mL of benzene was dropwise added to a solution of ArN-
HCH(Ph)CH(Ph)NHAr, Ar = 2,4,6-Me3C6H2 (116 mg, 0.258
mmol) in 10 mL benzene at room temperature. The reaction
solution was stirred for 6 h at room temperature. The color of
reaction mixture was changed from colorless to yellowish or-
ange, and then all volatiles were evaporated. The resulting oily
compound was washed with hexane (1 mL × 3). After drying
1
bath. The rates of the reactions were monitored by H NMR
spectroscopy. Yield of product 6aa was determined by the in-
tegration of 1H NMR signals of phenanthrene and
CyNCH(Ar)Cy.
X-Ray crystallographic analysis.
All crystals were handled similarly. The crystals were mounted
on the CryoLoop (Hampton Research Corp.) with a layer of
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Journal of the American Chemical Society
Fang, C.-H.; Li, C.-Y.; Ong, T.-G.; Yap, G. A. J. Am. Chem. Soc. 2010,
light mineral oil and placed in a nitrogen stream at 113(1) K.
132, 11887-11889. (c) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama,
T. J. Am. Chem. Soc. 2010, 132, 13666-13668. (d) Lee, W.-C.; Chen,
C.-H.; Liu, C.-Y.; Yu, M.-S.; Lin, Y.-H.; Ong, T.-G. Chem. Commun.
2015, 51, 17104-17107. (e) Singh, V.; Nakao, Y.; Sakaki, S.; Desmukh,
M. M. J. Org. Chem. 2017, 82, 289-301.
(5) Pd catalyzed pyridiyl C—H addition into unsaturated non polar
bonds: Ye, M.; Gao, G.-L.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133,
6964-6967.
(6) Some examples of Co catalyzed alkylation of pyridines and quin-
olones: (a) Andou, T.; Saga, Y.; Komai, H.; Matsunaga, S.; Kania, M.
Angew. Chem., Int. Ed. 2013, 52, 3213-3216. (b) Yamamoto, S.; Saga,
Y.; Andou, T.; Matsunaga, S.; Kanai, M. Adv. Synth. Catal. 2014, 356,
401-405.
1
2
3
4
5
6
7
8
All measurements were made on a Rigaku XtaLAB P200 dif-
fractometer using multi-layer mirror monochromated Mo-K
(0.71075 Å) radiation. Crystal data and structure refinement
parameters were listed in Table S5. The structures were solved
by SIR-9231 and refined on F2 by full-matrix least-squares
method, using SHELXL-2013.32 Non-hydrogen atoms were an-
isotropically refined. H-atoms were included in the refinement
on calculated positions riding on their carrier atoms. The func-
tion minimized was [Σw(Fo2- Fc2)2] (w = 1 / [σ2 (Fo2) + (aP)2 +
bP]), where P = (Max(Fo2,0) + 2Fc2) / 3 with σ2(Fo2) from
counting statistics. The function R1 and wR2 were (Σ||Fo| -
|Fc||) / Σ|Fo| and [Σw(Fo2 – Fc2 )2 / Σ(wFo4)]1/2, respectively.
The ORTEP-3 program was used to draw the molecule.33
9
10
11
12
13
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16
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22
23
24
25
26
27
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31
32
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35
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37
38
39
40
41
42
43
44
45
46
47
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60
(7) Cr catalyzed pyridiyl C—H addition into unsaturated non polar
bonds: Li, Y.; Deng, G.; Zeng, X. Organometallics 2016, 35, 747-750.
(8) Some examples of late transition metal catalyzed C—H addition
of N-heteroaromatics into unsaturated non polar bonds: (a) Cho, S. H.;
Hwang, S, J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254-9256. (b)
Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400-402. (c)
Huckins, J. R.; Bercot, E. A.; Thiel, O. R.; Hwang, T.-L.; Bio, M. M.
J. Am. Chem. Soc. 2013, 135, 14492-14495. (d) Zhou, B.; Chen, H.;
Wang, C. J. Am. Chem. Soc. 2013, 135, 1264-1267. (e) Wong, M. Y.;
Yamakawa, T.; Yoshikai, N. Org. Lett. 2015, 17, 442-445. (f) Yahaya,
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N. E.; Whitwood, A. C.; Lynam, J. M.; Fairlamb, I. J. S. Angew. Chem.,
Int. Ed. 2016, 55, 12455-12459.
(9) Recent reviews of σ-bond metathesis and catalytic reactions me-
diated by early transition metals: (a) Waterman, R. Organometallics
2013, 32, 7249-7263. (b) Tsurugi, H.; Yamamoto, K.; Nagae, H.;
Kaneko, H. Mashima, K. Dalton Trans. 2014, 43, 2331-2343.
(10) Some examples of group 3 metals and lanthanides catalyzed
pyridyl C—H bond addition into unsaturated non polar bonds: (a) Deel-
man, B.-J.; Stevels, W. M.; Teuben, J. H.; Lakin, M. T.; Spek, A. L.
Organometallics 1994, 13, 3881-3891. (b) Kaneko, H.; Nagae, H.;
Tsurugi, H.; Mashima, K. J. Am. Chem. Soc. 2011, 133, 19626-19629.
(c) Guan, B.-T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086-18089.
(d) Luo, G.; Luo, Y.; Qu, J.; Hou, Z. Organometallics 2012, 31, 3930-
3937.
(11) Some examples of group 4 metal catalyzed pyridyl C—H bond
addition into unsaturated non polar bonds: (a) Nugent, W. A.; Ovenall,
D. W.; Holmes, S. J. Organometallics 1983, 2, 161-162. (b) Jordan, R.
F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778-779. (c) Rodewald,
S.; Jordan, R. F. J. Am. Chem. Soc. 1994, 116, 4491-4492.
(12) Some reviews of C—H bond addition into unsaturated polar
bonds: (a) Colby, D. A.; Tsai, A. S.; Bergmna, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814-825. (b) Yan, G.; Wu, X.; Yang, M. Org.
Biomol. Chem. 2013, 11, 5558-5578. (c) Zhang, X. -S.; Chen, K.; Shi,
Z. -J. Chem. Sci. 2014, 5, 2146-2159. (d) Yand, L.; Huang, H. Chem.
Rev. 2015, 115, 3468-3517. (e) Hummel, J. R.; Boerth, J. A.; Ellman,
J. A. Chem. Rev. 2017, 117, 9163-9227.
(13) Some examples of catalytic C-H bond addition of N-heteroaro-
matics into unsaturated polar bonds, (a) Tsai, A. S.; Tauchert, M. E.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248-1250.
(b) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen,
K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115-2119. (c) Gao, K.;
Yoshikai, N. Chem. Commun. 2012, 48, 4305-4307. (d) Yoshino, T.;
Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed. 2013,
57, 2207-2211. (e) Wicker, B. F.; Scott, J.; Fout, A. R.; Pink, M.; Min-
diola, D. J. Organometallics 2011, 30, 2453-2456. (f) Fukumoto, Y.;
Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S. Angew. Chem., Int.
Ed. 2002, 41, 2779-2781. (g) Moore, E. J.; Pretzer, W. R.; O’Connell,
T. J.; Harris, J.; LaBounty, L.; Chou, L.; Grimmer, S. S. J. Am. Chem.
Soc. 1992, 114, 5888-5890. (h) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2,
488-493.
ASSOCIATED CONTENT
Experimental details, kinetic study, NMR spectra of products,
crystal data and data collection parameters, and CIF file giving
data for complexes 11 and 12. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* mashima@chem.es.osaka-u.ac.jp
* tsurugi@chem.es.osaka-u.ac.jp
Notes
ACKNOWLEDGMENT
A. K. acknowledges to the JICA Friendship program of Osaka Uni-
versity – IIT Hyderabad. H. N. acknowledges a financial supported
by JSPS KAKENHI Grant Number JP16H06934, a Grant-in-Aid
for Research Activity Start-up of The Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan. H. T. acknowledges
a
financial supported by JSPS KAKENHI Grant Number
15KT0064, a Grant-in-Aid for Scientific Research (B) of The Min-
istry of Education, Culture, Sports, Science, and Technology, Japan.
We appreciate Prof. Laurent Maron (University of Toulouse) for
his fruitful discussion and suggestions.
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