Aminomethylation reaction of Ortho -pyridyl C-H bonds catalyzed by group 3 metal triamido complexes

Article abstract of DOI:10.1021/ja511964k

Tris[N,N-bis(trimethylsilyl)amido] complexes of group 3 metals, especially yttrium and gadolinium, served as catalysts for ortho-C-H bond addition of pyridine derivatives and N-heteroaromatics into the C=N double bond of nonactivated imines to afford the corresponding aminomethylated products. Addition of catalytic amounts of secondary amines, such as dibenzylamine, dramatically improved the catalytic activity through the formation of a mixed ligated complex such as [(Me₃Si)₂N]₂Y(NBn₂)(THF) (4). Furthermore, kinetic studies using the isolated complex 4 provided a plausible reaction mechanism by which coordination of two pyridine derivatives afforded a penta-coordinated species as a key step.

Full text of DOI:10.1021/ja511964k

Communication
pubs.acs.org/JACS
Aminomethylation Reaction of ortho-Pyridyl C−H Bonds Catalyzed
by Group 3 Metal Triamido Complexes
Haruki Nagae, Yu Shibata, Hayato Tsurugi,* and Kazushi Mashima*
Department of Chemistry, Graduate School of Engineering Science, Osaka University and CREST, JST, Toyonaka, Osaka 560-8531,
Japan
S
* Supporting Information
Scheme 1. Catalytic Pyridyl C−H Bond Addition Reactions
into Unsaturated Bonds
ABSTRACT: Tris[N,N-bis(trimethylsilyl)amido] com-
plexes of group 3 metals, especially yttrium and
gadolinium, served as catalysts for ortho-C−H bond
addition of pyridine derivatives and N-heteroaromatics
into the CN double bond of nonactivated imines to
afford the corresponding aminomethylated products.
Addition of catalytic amounts of secondary amines, such
as dibenzylamine, dramatically improved the catalytic
activity through the formation of a mixed ligated complex
such as [(Me3Si)2N]2Y(NBn2)(THF) (4). Furthermore,
kinetic studies using the isolated complex 4 provided a
plausible reaction mechanism by which coordination of
two pyridine derivatives afforded a penta-coordinated
species as a key step.
yridine derivatives are important structural motifs that exist
Pin a number of natural products, medicinal agents, ligands,
and functional materials.1 Despite the development of several
synthetic methods to date, the recent trend toward transition-
metal-catalyzed C−H bond activation followed by functionaliza-
tion is regarded as the most direct synthetic protocol to introduce
functional groups on the pyridine skeleton in terms of atom and
step economical processes.2 Upon applying late transition-metal
catalysts, the first step is typical oxidative addition of the C−H
bond of the pyridine onto a coordinatively unsaturated low-
valent metal center to generate a pyridyl-hydride-metal species,
(py)M(H), to which sequential 1,2-addition reaction of nonpolar
CC double bonds and CC triple bonds to a hydride-metal
moiety affords pyridyl-metal species with M-alkyl and alkenyl
bonds, respectively, and then reductive elimination produces
alkyl- and alkyenyl-substituted pyridine derivatives (Scheme
1).2−6 Similarly, some early transition-metal complexes are
reported to proceed via a σ-bond metathesis reaction with
pyridine to give the corresponding pyridyl-metal species, to
which a nonpolar CC double bond is inserted to give
alkylpyridine compounds catalytically (Scheme 1, eq 1).7,8
In contrast, although it is perceived that the C−H bond
addition to CX bond (X = N, O) of imines and carbonyl
compounds expands the substrate scope to provide heteroatom-
containing pyridine derivatives, no such catalytic coupling
reaction has been achieved.9−11 Such limitation is attributed to
the undesired regioselectivity of CX bond insertion into the
hydride-metal moiety to form new C−C bonds for late
transition-metal complexes. On the other hand, although it was
reported that a M−N bond of groups 3 and 4 metals activates the
C−H bond of pyridines through a σ-bond metathesis mechanism
in a stoichiometric manner,12 an addition reaction of the
resulting pyridyl-metal species of groups 3 and 4 metals into a
polar CN double bond of imines in both a stoichiometric and
catalytic manner has not been achieved and remains particularly
challenging. We thus anticipated that amido complexes of group
3 metals could potentially act as catalysts by activating the ortho-
C−H bond of pyridine derivatives by their M−N bonds and
reproducing the M−N bonds by subsequent insertion of the
resulting pyridyl-metal species into the CN double bond of
imines. Herein, we report the first catalytic addition reaction of
pyridine derivatives to nonactivated imines as mediated by
triamido complexes of group 3 metals (Scheme 1, eq 3).
When 2-phenylpyridine (1a) was treated with N,1-dicyclohex-
ylmethanimine (2a) (2 equiv) in the presence of Y[N(SiMe3)2]3
(10 mol %) in C6D6 at 100 °C for 24 h, the corresponding
pyridine aminomethylated product 3aa was obtained in 46%
yield (entry 1). In this aminomethylation reaction, the phenyl
ring of 2-phenylpyridine did not react, but the ortho-position of
the pyridine ring of 2-phenylpyridine was regioselectively
activated.13 A noteworthy difference was that late transition-
metal complexes predominantly assisted the catalytic amino-
methylation reaction with imines at the ortho-position of the
phenyl ring of 2-phenylpyridine, where the pyridine moiety
worked as a directing group to the metal center.14 For the test
reaction under the same conditions, we examined various rare-
Received: November 25, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja511964k
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Journal of the American Chemical Society
Communication
earth metal amidos, M[N(SiMe3)2]3 (M = Yb, Gd, Sm, Nd, La),
as catalysts. The ionic size of lanthanides affected the catalytic
performance: lanthanide complexes of smaller (Yb) and larger
(La) ionic size exhibited almost the same lower catalytic activities
(16% and 20% yield, respectively), while complexes of ionic radii
similar to yttrium ion exhibited moderate activities (41−59%,
entries 3−5) equal to or better than that of the yttrium complex.
Among them, Gd[N(SiMe3)2]3 was the best catalyst (59%, entry
3). Thus, moderately sized lanthanide metals might be required
to show enough catalytic activity.
Table 2. Scope and Limitation of Pyridine Derivatives and N-
Heteroaromatics
We then investigated the additive effects of secondary amines
because product 3aa is one of secondary amines. Addition of
tetramethylpiperidine (HTMP) and dicyclohexylamine
(HNCy2), both of which are bulky secondary amines typically
used for activating C−H bonds,12 to the reaction using
Gd[N(SiMe3)2]3 slightly increased the yield of 3aa to 65% and
64%, respectively (entries 7 and 8). The addition of dibenzyl-
amine (HNBn2) to the reaction mixture of Gd[N(SiMe3)2]3
effectively accelerated the aminomethylation reaction to produce
3aa in 86% yield (entry 9). We further conducted the reaction
under the conditions of Gd[N(SiMe3)2]3 and dibenzylamine to
reach 90% yield of 3aa upon increasing the substrate
concentration (entries 10 and 11). The same tendency was
observed for the system of Y[N(SiMe3)2]3 where HNBn2 was the
most effective.13 Thus, dibenzylamine was selected as the best
amine additive for this catalytic reaction.
Table 1. Screening of Catalysts
a
b
c
Isolated yield. Reaction for 48 h. 5 mol % of [Gd] was used.
position C−H bond of 2-phenylthiazole reacted with 2a to form
an aminomethylated product 3ga in 67% yield (entry 6).
Secondary and tertiary alkyl groups as well as aryl groups were
applicable as substituents at the imine-carbon and -nitrogen
atoms of the substrates (Table 3). When isopropyl, 1-adamantyl,
a
entry
Ln
solv.
conc., M
additive
yield (%)
1
2
Y
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
Tol
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.5
−
−
−
−
−
46
16
59
43
41
20
65
64
86
87
Yb
Gd
Sm
Nd
La
Table 3. Scope and Limitation of Imine Substrates
3
4
5
6
−
7
Gd
Gd
Gd
Gd
Gd
HTMP
HNCy2
HNBn2
HNBn2
HNBn2
8
a
R1
iPr
R2
product yield (%)
9
entry
bc
,
10
1
2
3
4
5
6
7
8
9
Cy
Cy
(2b)
(2c)
(2d)
(2e)
(2f)
(2g)
(2h)
(2j)
(2j)
3ab
3ac
3ad
3ae
3af
66
93
64
81
81
57
76
60
35
b
de
,
11
Tol
90
Ad
tBu
a
1H NMR yield 1,1,2,2-Cl4-ethane was used as internal standard.
Isolated yield.
de
,
Cy
b
be
,
CH(Me)Ph
Cy
de
,
4-OMe-2-Me-C6H3
Cy
iPr
de
,
Cy
Cy
Cy
3ag
3ah
3ai
de
,
c-C5H9
CHEt2
Ph
Under the optimized reaction conditions, we conducted the
bc
,
aminomethylation of heteroaromatic compounds 1b−1g with
the imine 2a, and the results are summarized in Table 2. A series
of 2-alkylpyridines 1b−1d was converted to the corresponding
coupling products 3ba−3da in moderate to good yields (entries
1−3). In these cases, no coupling reaction was observed at the
C(sp3)-H bond of the alkyl moiety, even at the benzylic
position.8c,15 When 1-phenylisoquinoline was used as a substrate,
a C−H bond of the isoquinoline ring was activated at the 3-
position to afford 3ea in 70% yield (entry 4). N-Methylbenzi-
midazole reacted efficiently at the 2-position to produce 3fa in
94% yield (entry 5), whereas related benzoazoles, benzoxazole
and benzothiazole, were not applicable in this reaction. The 4-
de
,
Cy
3aj
a
b
Isolated yield. 10 mol % of Gd[N(SiMe3)2]3/HNBn2 was used at
c
d
100 °C. Reaction for 36 h. 20 mol % of Y[N(SiMe3)2]3/HNBn2 was
used at 130 °C Reaction for 96 h.
e
tert-butyl, 1-phenylethyl, and aryl groups were attached to the
nitrogen atom of the imines, the corresponding aminoalkylated
products 3ab−3af were obtained in good yield (entries 1−5).
Although the reaction with N-cyclohexylbenzylidenimine (2j)
was slow and the product yield was moderate (entry 9), imines
2g−2i having secondary alkyl groups at the imine carbon were
B
DOI: 10.1021/ja511964k
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Journal of the American Chemical Society
Communication
efficiently transformed to the corresponding aminoalkylated
products 3ag−3ai (entries 6−8). In contrast, when imines
having primary alkyl groups at the imine-nitrogen and -carbon
atoms were applied to the reaction, the corresponding
aminoalkylated products were obtained in low yield, probably
due to the facile coordination of the reaction products to the
metal center.
phenylpyridine concentration. Thus, the reaction rate is
presented as [4][pyridines]2[imine]0. To gain insight into the
mechanism, we performed a deuterium-labeling experiment
using 2-phenylpyridine-d9. The KIE value was 3.19, suggesting
that C−H bond activation was involved at the rate-determining
step. The rate of the consumption of 2-phenylpyridine catalyzed
1
by 4 was also monitored by H NMR spectroscopy over a
To gain insight into the reaction mechanism, yttrium
temperature ranging from 89 to 110 °C under the optimized
conditions shown in Table 2. Eyring kinetic analyses yielded the
following activation parameters: ΔH⧧ = 48.8 1.5 kJ mol−1, ΔS⧧
= −153.9 4.0 au, and ΔG⧧(298 K) = 94.6 2.7 kJ mol−1. The
negative ΔS⧧ value is consistent with the highly ordered
transition state involving the intrinsic coordination of two 2-
phenylpyridine to the metal center.
Based on the isolation of [(SiMe3)2N]2YNBn2(THF) (4) and
kinetic study of the aminomethylation using the isolated complex
4, we propose a plausible mechanism as shown in Scheme 2.
1
complexes were used to monitor the reaction by H NMR
measurement,13 as the Gd complex is paramagnetic. The reaction
catalyzed by Y[N(SiMe3)2]3 without any amine additives led to
<10% yield of 3aa, even after 10 h. In good accordance with the
additive effects of HNBn2 to enhance the catalytic activity, the
reaction by Y[N(SiMe3)2]3 and HNBn2 proceeded smoothly
even at the initial stage. Based on such clear evidence, we
expected that a mixed-ligated yttrium amido complex might be
generated as a catalytically active species. In fact, we mixed
Y[N(SiMe3)2]3 and HNBn2 to give a complicated mixture, from
which we could not isolate any identical yttrium compounds.
Alternatively, when we treated Y(CH2SiMe3)3(THF)2 with 2
equiv of HN(SiMe3)2 and 1 equiv of HNBn2, a mixed ligand
complex, [(Me3Si)2N]2Y(NBn2)(THF) (4), was isolated and
crystallographically characterized (Figure 1). Remarkably, the
Scheme 2. Proposed Reaction Mechanism
Figure 1. Molecular structure of complex 4 with 30% thermal ellipsoids.
All H atoms have been omitted for clarity. Selected bond distances (Å)
and angles (deg): YN1, 2.251(2); YN2, 2.255(2); YN3,
2.1754(19); YSi1, 3.2559(15); YSi4, 3.3370(16); YN1Si1,
109.59(10); YN1Si2, 129.73(10); YN2Si3, 123.41(11); Y
N2Si4, 113.60(11).
Catalytic reaction of 1a with 2a using 4 is initiated by the
coordination of 2 equiv of 2-phenylpyridine to the yttrium center
of the mixed ligated triamido complex A derived by the
dissociation of THF from 4 to form the penta-coordinated
species B. The second-order rate dependence on the
concentration of 2-phenylpyridine indicates the formation of B
in this catalytic cycle. As model catalytically active species, we
added pyridine (excess) and 2,2′-bipyridyl (1 equiv) to complex
4. Isolation and structural characterization of tetra-coordinated
and penta-coordinated [(SiMe3)2N]2YNBn2(L) complexes (5: L
= py, 6: L = 2,2′-bipyridyl) suggests the coordination of 2 equiv
of substrates to the metal center just before ortho-C−H bond
activation.13 Ortho-C−H bond activation of the pyridine moiety
of 1a by the amidometal moiety proceeds to form a η2-
pyridylmetal species C as the rate-determining step. The zero-
order kinetics of the imine 2a suggests that precoordination of 2a
is essential for the formation of D. The C−C bond formation
between the η2-pyridylmetal and the coordinated imine rapidly
occurs to form E, and subsequent protonation by the amine
regenerates the mixed ligated triamido complex species A and
yields the aminomethylated product 3aa. When the amino-
alkylated product 3aa was added to the reaction mixture (same
amount to catalyst), the reaction rate was almost the same as that
under normal conditions, suggesting that the catalytic cycle did
isolated complex 4 became a catalyst with similar reaction profile
as that of the in situ catalyst system of Y[N(SiMe3)2]3 and
HNBn2.13 While the presence of THF in the reaction mixture
(up to 5 equiv based on catalyst) did not affect the product yield,
the reaction in THF as the solvent resulted in low yield. Thus, the
sterically less-hindered dibenzylamido ligand might open the
active site by releasing THF, to which the substrates coordinated
to induce the activation of the C−H bond followed by the
insertion of imines.
With the isolated catalyst 4 in hand, we measured the reaction
rate law in relation to the concentrations of catalyst 4, 2-
phenylpyridine (1a), and N,1-dicyclohexylmethanimine (2a). A
first-order rate dependence on the catalyst concentration was
observed over a 4-fold range, indicating that the active species
was a monomeric species. The initial reaction rate did not
depend on the concentration of imine 2a in the range between
0.2 and 0.4 M, suggesting apparent zero-order dependence on
the imine concentration up to half-lives; however, excess
amounts of imine suppressed the reaction rate. Notably, the
reaction showed a second-order rate dependence on the 2-
C
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Journal of the American Chemical Society
Communication
Am. Chem. Soc. 2007, 129, 5332−5333. (b) Yotphan, S.; Bergman, R. G.;
Ellman, J. A. Org. Lett. 2010, 12, 2978−2981.
not involve product inhibition. Bulky substituents at the nitrogen
and carbon atoms of the aminoalkyl chain might lead to
irreversible dissociation of the aminoalkylated products from the
metal center.
(4) For some examples of Ni-catalyzed pyridyl C−H bond addition
into unsaturated bonds (a) Nakao, Y.; Yamada, Y.; Kashihara, N.;
Hiyama, T. J. Am. Chem. Soc. 2010, 132, 13666−13668. (b) Nakao, Y.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448−2449.
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A. J. Am. Chem. Soc. 2010, 132, 11887−11889.
In summary, we developed the first catalytic C−H bond
addition of pyridine derivatives coupled with a nonactivated C
N double bond to afford aminomethylated products of pyridines
using rather simple homoleptic rare-earth metal triamides. The
catalytic activity was dramatically improved by adding a catalytic
amount of dibenzylamine to generate a mixed ligated triamido
complex that opened the coordination site for the substrate.
Furthermore, several kinetic studies as well as the isolation of a
mixed ligand triamido complex, [(SiMe3)2N]2YNBn2(THF) (4)
as a catalytically active species, provided a plausible reaction
mechanism in which precoordination of two pyridine derivatives
generating penta-coordinated species is assumed to be involved
as a key step. Further development of this new catalytic reaction
is ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, catalysts screening, NMR spectra, kinetics
data and deuterium labeling experiments; CIF file giving for
complexes 4−6. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) For an example of catalytic C−H bond addition of N-
heteroaromatics into CO double bond by using Et3SiH (a) Fukumo-
to, Y.; Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S. Angew. Chem.,
Int. Ed. 2002, 41, 2779−2781. (b) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2,
488−493.
AUTHOR INFORMATION
Corresponding Authors
mashima@chem.es.osaka-u.ac.jp
tsurugi@chem.es.osaka-u.ac.jp
■
(11) For rare examples of catalytic C−H bond addition into CX
triple bond (a) 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. (b) Wicker, B. F.; Scott, J.; Fout, A. R.; Pink, M.; Mindiola,
D. J. Organometallics 2011, 30, 2453−2456.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) For two examples of pyridyl C−H bond activation by early
transition amido complexes (a) Jeganmohan, M.; Knochel, P. Angew.
Chem., Int. Ed. 2010, 49, 8520−8524. (b) Wunderlich, S. H.; Knochel, P.
Chem.Eur. J. 2010, 16, 3304−3307.
H.N. thanks the financial support by the JSPS Research
Fellowships for Young Scientists. Y.S. acknowledges to the
financial support by the JSPS Postdoctoral Fellowship. Thank to
Ms. Rika Miyake (Osaka University) for assistance of high-
resolution mass spectral measurements. H.T. acknowledges
financial support by a Grant-in-Aid for Young Scientists (A) of
The Ministry of Education, Culture, Sports, Science, and
Technology, Japan. This work was supported by the Core
Research for Evolutional Science and Technology (CREST)
program of the Japan Science and Technology Agency (JST),
Japan.
(13) See Supporting Information.
(14) For some examples of hydroarylation of imines (a) Tsai, A. S.;
Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011,
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R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482−1485. (d) Li, Y.;
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D
DOI: 10.1021/ja511964k
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX