Catalytic C-H bond addition of pyridines to allenes by a rare-earth catalyst

Article abstract of DOI:10.1002/chem.201501121

The catalytic C-H addition of pyridines to allenes has been achieved for the first time by using a half-sandwich scandium catalyst, thus constituting a straightforward and atom-economical route for the synthesis of alkenylated pyridine derivatives. The reaction proceeded regio- and stereoselectively, affording a new family of alkenylated pyridine compounds which are otherwise difficult to synthesize. A cationic Sc-η²-pyridyl species was isolated and confirmed to be a key catalyst species in this transformation.

Full text of DOI:10.1002/chem.201501121

DOI: 10.1002/chem.201501121
Communication
&
Synthetic Methods
Catalytic CÀH Bond Addition of Pyridines to Allenes by a Rare-
Earth Catalyst
Guoyong Song, Baoli Wang, Masayoshi Nishiura, and Zhaomin Hou*[a]
compound with an allene unit has not been reported previous-
Abstract: The catalytic CÀH addition of pyridines to al-
ly, although a large number of examples of allene insertion
lenes has been achieved for the first time by using a half-
into aromatic CÀH bonds are known.[5] The addition of a zirco-
sandwich scandium catalyst, thus constituting a straight-
nium pyridyl species formed by pyridine CÀH bond activation
forward and atom-economical route for the synthesis of
to 1,2-propadiene was reported previously, but the catalytic CÀ
alkenylated pyridine derivatives. The reaction proceeded
H alkenylation of a pyridine compound with an allene by a zir-
regio- and stereoselectively, affording a new family of alke-
conium complex seemed difficult.[6] We recently found that cat-
nylated pyridine compounds which are otherwise difficult
ionic half-sandwich rare-earth alkyls could serve as efficient
to synthesize. A cationic Sc-h2-pyridyl species was isolated
catalysts for the CÀH alkylation of aromatic compounds such
and confirmed to be a key catalyst species in this transfor-
as pyridines[2f,j] and anisoles[7] with various alkenes. In most
mation.
cases, the selectivity and functional group tolerance of the
rare-earth catalysts are different from those of late transition
metal catalysts. Encouraged by these results, we examined the
Pyridine units are among the most important heterocyclic
use of rare-earth catalysts for pyridine CÀH functionalization
structural motifs, existing widely in many natural products,
pharmaceuticals, ligands and functional materials.[1] The devel-
opment of efficient protocols for the synthesis of pyridine de-
rivatives has therefore received much current interest.[2,3] So
far, extensive studies on the CÀH alkylation of pyridines with
alkenes have been carried out as the most atom-economical
method for the synthesis of alkylated pyridine derivatives.[2] In
contrast, studies on the synthesis of alkenylated pyridine deriv-
atives by CÀH functionalization of pyridines have remained
very limited despite recent progress.[3] It was previously report-
ed that the CÀH addition of pyridines to alkynes catalyzed by
late transition metal catalysts such as ruthenium[3a] and nick-
el[3b,c] could give the corresponding alkenylated pyridine deriv-
atives, but this transformation suffered from poor regioselectiv-
ity when internal alkynes having two similar substituents were
used as substrates. The palladium-catalyzed oxidative coupling
of pyridines with alkenes was also reported to afford the alke-
nylated products,[3d] while this reaction is suitable only for al-
kenes having electron-withdrawing groups. The search for new
protocols for the efficient, selective synthesis of alkenylated
pyridine compounds is therefore of much interest and impor-
tance.
with allenes. Herein, we report, for the first time, the catalytic
CÀH addition of pyridines to allenes by a scandium catalyst.
This transformation is highly regio- and stereoselective, leading
to formation of a new family of alkenylated pyridine deriva-
tives which are otherwise difficult to synthesize. A cationic Sc-
h2-pyridyl complex was confirmed to be the true active catalyst
species, thus offering important information for understanding
the reaction mechanism.
On the basis of the screening of several different rare-earth
catalysts (see Supporting Information, Table S1), we chose the
combination of the half-sandwich scandium 1 (Scheme 1) and
[Ph3C][B(C6F5)4] as a catalyst to examine the reactions of various
pyridine derivatives (3) with cyclohexylallene (4a).
Scheme 1. Half-sandwich scandium dialkyl complexes with different cyclo-
pentadienyl (Cp) ligands.
In principle, the catalytic CÀH addition of pyridines to a C=C
double bond of allenes[4] could serve as an efficient and atom-
economical route for the synthesis of alkenylated pyridine de-
rivatives. However, such catalytic CÀH alkenylation of a pyridine
Some representative results are summarized in Table 1. In
the presence of 1 (5 mol%) and [Ph3C][B(C6F5)4] (5 mol%) in
toluene at 708C, the reaction proceeded regio- and stereose-
lectively, affording the corresponding branched alkenylation
product 5 through the addition of the pyridyl unit to the
middle carbon atom and the addition of a hydrogen atom to
the terminal carbon atom of the allene unit in an E-selective
fashion.[8] A broad range of substituted pyridines such as 2-pi-
[a] Dr. G. Song, Dr. B. Wang, Dr. M. Nishiura, Prof. Dr. Z. Hou
Organometallic Chemistry Laboratory and
RIKEN Center for Sustainable Resource Science
RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
E-mail: houz@riken.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501121.
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coline, 2-isopropylpyridine, 2,3-lutidine, 2,4-lutidine, and ring-
fused pyridine derivatives are suitable substrates for this cata-
lytic transformation.[9] Remarkably, the chloro-, bromo- and
iodo-substituents in the pyridine substrates survived the cata-
lytic reaction conditions, leading to selective formation of the
CÀH alkenylation products without dehalogenation (5e, 5 f, 5i
and 5j). 1-Methylisoquinoline and 3-methylisoquinoline were
also alkenylated selectively to give the expected products 5n
and 5o, respectively. In the case of 2-phenylpyridine, the steri-
cally demanding C5Me4(SiMe3)-ligated Sc catalyst 1 was less ef-
fective than the smaller C5H5-ligated analogue 2 for the forma-
tion of the expected product 5h,[10] probably owning to the
steric repulsion between the C5Me4(SiMe3) ligand in 1 and the
phenyl ring in 4h.[11]
Table 2. Catalytic CÀH addition of 2-ethylpyridine to various allenes.[a]
Table 1. Catalytic CÀH addition of various pyridines to cyclohexylallene.[a]
[a] General reaction conditions: 3a (0.4 mmol), 4 (0.8 mmol), 1 (5 mol%),
[Ph3C][B(C6F5)4] (5 mol%), toluene (2.0 mL), 708C, isolated yield. [b] TIP=
triisopropylsilyl. [c] 4y: diastereomeric ratio (d.r.)=60:40; 5y: d.r.=54:46.
catalyst 2 showed much better performance than 1 for the for-
mation of the expected alkenylation products (5y and 5z).[11]
The treatment of 2-ethylpyridine with a cholesteryl-substitut-
ed allene 4aa (d.r.=55:45) afforded the corresponding 2-pyri-
dylvinyl steroid compound in 92% yield in a highly regio- and
stereoselective manner (Scheme 2),[14] demonstrating that the
present CÀH alkenylation reaction could be applied to the syn-
thesis of pyridine derivatives bearing naturally occurring struc-
tures.
The reaction of [D7]2-methylpyridine ([D7]3b) and cyclohexy-
lallene afforded the CÀD addition product [D7]5b, in which
99% deuterium was incorporated at the methyl position
[Eq. (1)]. The reaction of a 1:1 mixture of 2-methylpyridine (3b)
[a] General reaction conditions: 3 (0.4 mmol), 4a (0.8 mmol, Cy=cyclo-
hexyl), 1 (5 mol%), [Ph3C][B(C6F5)4] (5 mol%), toluene (2.0 mL), 708C, iso-
1
lated yield. H NMR spectra of the crude products indicated that only the
E isomer was formed.
Table 2 summarizes the reactions of 2-ethylpyridine with var-
ious allenes.[12] The allene substrates having linear, branched
and cyclic substituents all afforded the corresponding alkenyla-
tion products in a highly regio- and stereoselective fashion.
Siloxy groups such as OSi(iPr)3 (5r and 5s) are compatible with
the catalyst system.[13] The reaction of 2-ethylpyridine with trie-
thylsilylallene also took place regio- and stereoselectively, af-
fording the corresponding silylalkenylation product 5x in 75%
yield. In the case of allenes having a sterically demanding sub-
stituent, such as menthylallene and phenylallene, the smaller
Scheme 2. The CÀH addition of 2-ethylpyridine to cholesteryl allene. The rel-
ative stereochemistry of 5aa was confirmed by an X-ray crystallographic
analysis (see the Supporting Information).
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and [D4]2-methylpyridine ([D4]3b) with cyclohexylallene cata-
lyzed by 1/[Ph3C][B(C6F5)4] yielded a mixture of the CÀH and
CÀD alkenylation products 5b and [D]5b with a KIE (kinetic
isotope effect) value of 5.6 [Eq. (2)], suggesting that CÀH bond
activation may be involved in the rate-determining step.[2j]
Figure 1. ORTEP drawing of the cationic part of 6a with thermal ellipsoids
set at the 30% probability level. Hydrogen atoms and the counter-anion
part [BPh4] were omitted for clarity. Selected bond lengths [Š] and angles
[8]: Sc1ÀN1 2.142(2), Sc1ÀC17 2.174(3); N1-Sc1-C17 36.38(9), N(1)-Sc(1)-O(1)
89.77(8), C(17)-Sc(1)-O(2) 96.10(10).
To gain more information on the active catalyst species and
mechanistic details, the stoichiometric reaction of 2-ethylpyri-
dine with a 1:1 reaction mixture of 1 and [Et3NH][BPh4] was
conducted in THF at 708C (Scheme 3).
to a C6D5Cl solution of the pyridyl complex 6a at either room
or higher temperatures (708C) did not give an isolable pure
product. Nevertheless, heating 6a with a 1:1 mixture of 2-eth-
ylpyridine (3a) and cyclohexylallene (4a) at 708C in C6D5Cl af-
forded almost quantitatively the alkenylation product 5a, with
6a remaining unchanged (Scheme 3). The transformation of
3a and 4a to 5a could be achieved catalytically in the pres-
ence of 6a (5 mol%, 48 h, 708C; 75% yield), demonstrating
that the isolated cationic Sc pyridyl complex 6a could serve as
a catalyst for the present transformation despite the presence
of two coordinating THF ligands.[16]
Scheme 3. Isolation and transformation of a cationic Sc-h2-pyridyl complex
6a.
A cationic half-sandwich Sc-h2-pyridyl complex 6a was iso-
lated in 90% yield, which after recrystallization from THF/
hexane afforded single crystals suitable for X-ray diffraction
studies. It was revealed that complex 6a is a separated ion-
pair complex, in which the Sc atom is bonded to one
C5Me4SiMe3, one pyridyl and two THF ligands, without direct
bonding interaction between the Sc atom and the borate
anion [BPh4]À (Figure 1).
The pyridyl unit is bonded to the Sc atom in an h2-(N,C)
fashion.[15] Kinetic studies on the transformation of 1 to 6a re-
vealed the activation parameters of DH° =22.85 kcalmolÀ1 and
DS° =À7.1 eu (see the Supporting Information). The relatively
small entropy of activation is in agreement with an intramolec-
ular process. The stoichiometric reactions of 1/[Et3NH][BPh4]
with 3b and [D7]3b gave a KIE value of 7.9 [Eq. (3)], suggest-
ing again that CÀH activation is involved in the rate-determin-
ing step while the coordination of a pyridine unit to scandium
should be quick. Addition of 1 equiv of cyclohexylallene (4a)
On the basis of the experimental results described above,
a possible reaction mechanism for the present catalytic CÀH al-
kenylation of pyridines with allenes is proposed as shown in
Scheme 4. The sequential reaction of 1 with [Ph3C][B(C6F5)4]
and a pyridine compound 3 should generate a cationic scandi-
um pyridyl species such as A. The approach of an allene com-
pound 4 to A could take place through coordination of the
terminal C=C double bond to the Sc atom to afford B, in
which the substituent R’ in the allene unit should be directed
away from the pyridyl group to avoid steric repulsion. The ad-
dition of the pyridyl unit to the coordinated C=C double bond
would yield C, which on reaction with another molecule of
a pyridine compound 3 (CÀH deprotonation, D) could give the
alkenylated pyridine derivative 5 and regenerate A. Obviously,
the regio- and stereochemistry of the alkenylation product 5
should be governed by the coordination of the allene unit to
the metal center and the subsequent intramolecular migration
of the pyridyl group in B.
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B. Wang, M. Nishiura, Z. Hou, Angew. Chem. Int. Ed. 2013, 52, 4418;
Angew. Chem. 2013, 125, 4514; i) T. Andou, Y. Saga, H. Komai, S. Matsu-
naga, M. Kanai, Angew. Chem. Int. Ed. 2013, 52, 3213; Angew. Chem.
2013, 125, 3295; j) G. Song, W. W. N. O, Z. Hou, J. Am. Chem. Soc. 2014,
136, 12209; for a review, see: k) Y. Nakao, Synthesis 2011, 3209.
[3] For examples of CÀH alkenylation of pyridines, see a) M. Murakami, S.
Hori, J. Am. Chem. Soc. 2003, 125, 4720; b) Y. Nakao, K. S. Kanyiva, T.
Hiyama, J. Am. Chem. Soc. 2008, 130, 2448; c) C.-C. Tsai, W.-C. Shih, C.-H.
Fang, C.-Y. Li, T.-G. Ong, G. P. A. Yap, J. Am. Chem. Soc. 2010, 132, 11887;
d) M. Ye, G.-L. Gao, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 6964; e) Y.
Goriya, C. V. Ramana, Chem. Eur. J. 2012, 18, 13288.
[4] Selected reviews on the use of allenes as building blocks in organic
synthesis: a) A. Hoffmann-Rçder, N. Krause, Angew. Chem. Int. Ed. 2002,
41, 2933; Angew. Chem. 2002, 114, 3057; b) S. Ma, Chem. Rev. 2005, 105,
2829; c) T. Bai, S. Ma, G. Jia, Coord. Chem. Rev. 2009, 253, 423; d) J.
Le Bras, J. Muzart, Chem. Soc. Rev. 2014, 43, 3003.
[5] For examples, see: a) Y. Kuninobu, P. Yu, K. Takai, Org. Lett. 2010, 12,
4274; b) D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2010, 49, 8181;
Angew. Chem. 2013, 122, 8357; c) H. Wang, F. Glorius, Angew. Chem. Int.
Ed. 2012, 51, 7318; Angew. Chem. 2012, 124, 7430; d) Y. J. Zhang, E.
Skucas, M. J. Krische, Org. Lett. 2009, 11, 4248; e) R. Zeng, C. Fu, S. Ma, J.
Am. Chem. Soc. 2012, 134, 9597; f) B. Ye, N. Cramer, J. Am. Chem. Soc.
2013, 135, 636; g) R. Zeng, S. Wu, C. Fu, S. Ma, J. Am. Chem. Soc. 2013,
135, 18284.
Scheme 4. A possible catalytic cycle.
[6] A. S. Guram, R. F. Jordan, Organometallics 1991, 10, 3470.
[7] J. Oyamada, Z. Hou, Angew. Chem. Int. Ed. 2012, 51, 12828; Angew.
Chem. 2012, 124, 13000.
In summary, we have demonstrated that cationic half-sand-
wich scandium alkyl species can serve as an excellent catalyst
for the CÀH addition of pyridines to various terminal allenes in
a regio- and stereoselective fashion, thus constituting the first
example of the catalytic CÀH addition of pyridines to allenes
as well as an atom-economical route for the synthesis of alke-
nylated pyridine derivatives. Functional groups such as halo-
gens and siloxy units and some naturally occurring moieties
are compatible with this catalyst system. This protocol can
yield a new family of alkenylated pyridine compounds which
were difficult to prepare previously. The isolation and reactivity
investigation of the cationic pyridyl complex 6a together with
related kinetic studies have offered important information for
understanding the mechanistic details.
[8] The neutral complex 1 alone did not show any catalytic activity, sug-
gesting that a cationic scandium alkyl species is essential in the present
transformation. The analogous yttrium and gadolinium complexes were
not effective under the same conditions, in agreement with their activi-
ty observed previously in olefin polymerization. For related rare-earth-
catalyzed olefin polymerization, see: a) M. Nishiura, Z. Hou, Nat. Chem.
2010, 2, 257; b) Y. Luo, J. Baldamus, Z. Hou, J. Am. Chem. Soc. 2004, 126,
13910.
[9] In the case of unsubstituted pyridine, the alkenylation reaction did not
occur probably because the coordination of pyridine (with less steric
hindrance) to the scandium ion is too strong to allow access of the
allene (4) to the metal center, as observed previously. See also refs. [2f]
and [2j].
[10] It is also noteworthy that the product 5h formed by CÀH alkenylation
at the pyridine unit is the only detectable product. This is in contrast
with late transition-metal-catalyzed reactions of 2-phenylpyridine, in
which CÀH bond activation usually took place at the phenyl ring rather
than at the pyridine group. For reviews, see: a) X. Chen, K. M. Engle, D.-
H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; Angew. Chem.
2009, 121, 5196; b) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1147; c) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110,
624; d) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651.
[11] The catalyst species (a cationic half-sandwich scandium alkyl or pyridyl
species) bearing a bulkier Cp ligand may show higher stability and have
a longer lifetime, thus giving a higher product yield when the reaction
substrates do not have much steric hindrance. However, in the case of
more sterically demanding substrates, a catalyst having a smaller Cp
ligand could show higher activity and give a higher yield because of
less steric repulsion between the catalyst and the substrate, even if it
has a shorter lifetime.
Acknowledgements
Financial support by a grant-in-aid for scientific research (S)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan (No. 26220802) is gratefully acknowl-
edged. G.S. thanks RIKEN for a FPR fellowship.
Keywords: alkenylation · allenes · CÀH addition · pyridines ·
scandium
[12] For the synthesis of allene compounds, see: a) S.-S. Ng, T. F. Jamison,
Tetrahedron 2006, 62, 11350; b) Z. Li, C. Yang, H. Zheng, H. Qiu, G. Lai, J.
Organomet. Chem. 2008, 693, 3771; c) J. Kuang, S. Ma, J. Org. Chem.
2009, 74, 1763.
[13] M. Takimoto, S. Usami, Z. Hou, J. Am. Chem. Soc. 2009, 131, 18266.
[14] The two stereoisomers 6aa and 6aa’ were separated by chromatogra-
phy in a 1:1 ratio.
[15] For examples of metal-h2-pyridyl complexes, see: a) M. E. Thompson,
S. M. Baxter, A. R. Bulls, B. J. Burger, M. C. Nolan, B. D. Santarsiero, W. P.
Schaefer, J. E. Bercaw, J. Am. Chem. Soc. 1987, 109, 203; b) R. Duchateau,
E. A. C. Brussee, A. Meetsma, J. H. Teuben, Organometallics 1997, 16,
5506; c) G. Zhu, J. M. Tanski, D. G. Churchill, K. E. Janak, G. Parkin, J. Am.
Chem. Soc. 2002, 124, 13658; d) O. V. Ozerov, M. Pink, L. A. Watson, K. G.
Caulton, J. Am. Chem. Soc. 2004, 126, 2105; e) S. Arndt, B. R. Elvidge,
[1] a) C. A. Ramsden, J. A. Joule, V. V. Zhdankin, A. R. Katritzky, Handbook of
Heterocyclic Chemistry, 3rd ed., Elsevier, San Diego, 2010; b) B. J. Holli-
day, C. A. Mirkin, Angew. Chem. Int. Ed. 2001, 40, 2022; Angew. Chem.
2001, 113, 2076; c) J. P. Michael, Nat. Prod. Rep. 2005, 22, 627; d) D. G.
Kurth, M. Higuchi, Soft Matter 2006, 2, 915.
[2] For examples of catalytic CÀH addition of pyridines to alkenes leading
to formation of alkylated pyridine derivatives, see: a) R. F. Jordan, D. F.
Taylor, J. Am. Chem. Soc. 1989, 111, 778; b) B.-J. Deelman, W. M. Stevels,
J. H. Teuben, M. T. Lakin, A. L. Spek, Organometallics 1994, 13, 3881; c) S.
Rodewald, R. F. Jordan, J. Am. Chem. Soc. 1994, 116, 4491; d) J. C. Lewis,
R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2007, 129, 5332; e) Y.
Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J. Am. Chem. Soc. 2010, 132,
13666; f) B.-T. Guan, Z. Hou, J. Am. Chem. Soc. 2011, 133, 18086; g) G.
Luo, Y. Luo, J. Qu, Z. Hou, Organometallics 2012, 31, 3930; h) B.-T. Guan,
Chem. Eur. J. 2015, 21, 8394 – 8398
www.chemeurj.org
8397
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
P. M. Zeimentz, T. P. Spaniol, J. Okuda, Organometallics 2005, 24, 793.
See also: refs. [2c] and [6].
Y. Luo, M. Nishiura, Z. Hou, Angew. Chem. Int. Ed. 2007, 46, 1909; Angew.
Chem. 2007, 119, 1941.
[16] The isolated cationic rare-earth complexes bearing THF ligands often
lose catalytic activity. For examples, see: a) X. Li, M. Nishiura, L. Hu, K.
Mori, Z. Hou, J. Am. Chem. Soc. 2009, 131, 13870; b) L. Zhang, T. Suzuki,
Received: March 23, 2015
Published online on April 21, 2015
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