Controlled regiodivergent C-H bond activation of imidazo[1,5-a]pyridine via synergistic cooperation between aluminum and nickel

Article abstract of DOI:10.1021/ol502314p

The catalytic method features a cooperative interaction between Ni and Al imparting remote C-H alkenylation at the C5 position of imidazo[1,5-a]pyridine with alkynes at mild conditions. Exclusion of AlMe₃ switches the selectivity to the C3 position. Reactions with styrene and other olefinic substrates affording C5-adducts by Ni/Al catalysis are also included.

Full text of DOI:10.1021/ol502314p

Letter
pubs.acs.org/OrgLett
Controlled Regiodivergent C−H Bond Activation of
Imidazo[1,5‑a]pyridine via Synergistic Cooperation between
Aluminum and Nickel
Ming-Shiuan Yu,† Wei-Chih Lee, Chih-Hao Chen, Fu-Yu Tsai, and Tiow-Gan Ong*
,‡
†
†,§
§
,†
†
Institute of Chemistry, Academia Sinica, Nangang, Taipei 11529, Taiwan, Republic of China
‡
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, Republic of China
§
Department of Molecular Science and Engineering, National Taipei University of Technology, Taipei 10608, Taiwan, Republic of
China
*
S Supporting Information
ABSTRACT: The catalytic method features a cooperative inter-
action between Ni and Al imparting remote C−H alkenylation at the
C5 position of imidazo[1,5-a]pyridine with alkynes at mild
conditions. Exclusion of AlMe switches the selectivity to the C3
3
position. Reactions with styrene and other olefinic substrates
affording C5-adducts by Ni/Al catalysis are also included.
7
8
ver the past decade, transition metal promoted C−H bond
ularly for the heteroarene moiety. More recently, our group,
9
10
O
activation has emerged as a powerful synthetic strategy,
Nakao, Hiyama, and Chatani utilized bifunctional catalysts
consisting of Ni and a Lewis acid to derivatize the C−H bond of
pyridines and azoles in a regioselective manner. Particularly,
Driver and co-workers reported the C7-functionalization of
triazolopyridine by nickel in the presence of AlMe3.
Encouraged by these previous successes, we hypothesized that
avoiding additional steps associated with prefunctionalized
1
coupling partners. In this context, direct C−H activation of
heteroarenes like imidazo[1,5-a]pyridines has synthetic merits
7
h
and importance due to their potential applications in electronic
2
3
and photoresponsive materials, carbene-like ancillary ligand,
4
and various bioactive agents. Although significant progress has
been witnessed in Pd-mediated C−H activation of heterocyclic5
motifs, such as pyridines, indoles, caffeines, azoles, and furans,
work related to C−H functionalization of imidazo[1,5-a]pyridine
are scarce at this stage, for which the majority of their reactivities
the addition of Lewis acid AlMe would act cooperatively with
3
nickel to invoke an C−H alkenylation selectively at C5 position
(Scheme 1). At the same time, we expected that C−H activation
can be switched back to the C3 position without AlMe . Herein,
3
we report regiodivergent C−H alkenylation between C5 and C3
sites of imidazo[1,5-a]pyridine and derivatives using bimetallic
Ni/Al catalysis. The synthetic scope encompasses a myriad of
imidazo[1,5-a]pyridines, alkynes, and alkenes.
To test our initial hypothesis for C−H activation at the C3
position, we first examined alkenylation of imidazo[1,5-a]-
pyridine (1a) with 4-octyne (2a) in the presence of 10 mol % of
6
occurred exclusively at the C3 and C1 positions (Scheme 1). Yet,
no single example has been reported on direct C5 functionaliza-
tion of imidazo[1,5-a]pyridine. Therefore, a new paradigm for
C5−H bond activation would be highly desirable from academic
curiosity and synthetic perspective.
The use of nickel, a benign and low-cost transition metal, to
mediate C−H bond functionalization is less common, partic-
Ni(cod) in toluene at 40 °C with various supporting ligands
2
(
entries 1−6 in Table 1). Phosphine ligands PtBu and PPh were
3
3
Scheme 1. New Conceptual Approach
completely ineffective (entries 1−2). Both IMes and PCy
3
showed the best yield (99%) to afford C3 and C5 alkenylated
products (3aa and 4aa) in a high selectivity of 4:1 ratio (entries 3
and 6). Encouragingly, such high efficiency and C3 selectivity can
still be maintained when the catalyst loading was further reduced
to 5 mol % (entry 7). It should be noted that this direct C−H
functionalization of imidazo[1,5-a]pyridine was performed
under very mild conditions at ambient temperature. Finally,
Received: August 4, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502314p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Process for C3-Alkenylation of 1a
a]pyridines. At this stage, we wanted to examine the viability of
this catalytic reaction with various 1-aryl-imidazo[1,5-a]pyridine,
which may be useful for our future study in photosensitive
12
materials (entries 2−10, 1b−j). Overall, excellent yields
(
∼90%) were observed for substrates bearing electron-donating
groups (1c−e) with high C3 regioselectivity, but a moderate yield
(52%) was observed with a methoxy group (1f). Derivatives
containing electron-withdrawing groups like fluoro (1g), CF3
yield
b
ratio
(3:4)
entry [Ni] (mol %)
ligand (mol %)
T (°C)
(%)
1
2
3
4
5
6
7
10
10
10
10
10
10
5
PtBu (10)
40
40
40
40
40
40
rt
N.R.
3
(
1h), and ester (1i) were suitable with good yields and
PPh (20)
N.R.
99
3
regioselectivity. Such a catalysis promoted by nickel can also be
extended to heterocyclic-based substrates like thienyl (1m, 86%)
and furanyl (1n, 82%) with high efficiency except for the naphthyl
group (1l, 46%). Finally, imidazo[1,5-a]pyridines bearing
different styryl groups 1o−q (entries 15−17) gave the
corresponding products 3oa−3qa in moderate to good yields.
On the basis of our previous experience with Ni−Al
cooperative catalysis in C−H bond activation, introducing
bulky Lewis acid should in principle invoke a steric blockade
around C3’s vicinity of imidazo[1,5-a]pyridine, thus imparting a
possible activity at C5. Our initial screening efforts have focused
PCy (20)
4:1
2:1
3:1
4:1
4:1
3
c
amino-NHC (10)
99
IPr (10)
78
IMes (10)
IMes (5)
99
d
99 (96)
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 equiv), Ni(cod) , and
ligand in toluene (2 mL) for 12 h. Determined by H NMR using
mesitylene as the internal standard; isolated yield given in parentheses.
2
b
1
c
11 d
Amine-linked NHC. Run for 6 h.
a
Table 2. C3-Alkenylation of 1 with 2a
13
on few potential Lewis acids. We found AlMe was particularly
3
effective to direct C−H bond activation of 1a remotely at the C5
position with 2a, affording 4aa in a 98% yield with excellent
regioselectivity at room temperature (10:1 = 4aa:3aa) (entry 1,
Table 3). High yields (∼90%) with high C5 selectivity (average
a
Table 3. C5-Alkenylation of 1 with 2a
a
Reaction conditions: 1 (0.5 mmol), 2a (1.5 equiv), Ni(cod) (5 mol
2
b
%
), and IMes (5 mol %) in toluene (2 mL) at rt for 6 h. Isolated
c d
1
yield. Determined by H NMR. Run with 2a (1.1 equiv).
control experiments performed in the absence of nickel or IMes
did not afford any C−H alkenylated products.
With the optimized reaction conditions in hand, we examined
the reaction scope with various imidazo[1,5-a]pyridines (Table
a
Reaction conditions: 1 (0.5 mmol), 2a (1.5 equiv), Ni(cod) (5 mol
2
2). Excellent yields with high C3 regioselectivity were observed
%
), IMes (5 mol %), and AlMe (60 mol %) in toluene (2 mL) at rt
3
b c d
1
for 1a, 1b, and 1k, illustrating the nonsensitivity of the reaction
toward different substituents at C1 site of imidazo[1,5-
for 6 h. Isolated yield. Determined by H NMR. At 60 °C for 12 h.
e
Run with 2a (1.1 equiv).
B
dx.doi.org/10.1021/ol502314p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
1:9 = 3:4) were witnessed for substrates bearing various alkyl
Letter
a
∼
Table 5. Hydroheteroarylation of Olefins with 1
substituted 1-aryl-imidazo[1,5-a]pyridines (1b−d). Electron-
withdrawing groups consisting of fluoro (1g), CF (1h), CO Et
3
2
(
1i), and Ph (1j) gave excellent yields with high selectivity
(entries 7−10). Electron-donating groups like NMe (1e) and
2
OMe (1f) also afforded the corresponding products 4ea and 4fa
with high yields albeit at higher temperature 60 °C (entries 5−6).
In general, electronic perturbation of substrates did not seem to
affect much of the regioselectivity for C5 position. Likewise, such
C−H bond activation at C5 position could also be extended to a
more π-conjugated system like 1-naphthyl (1l), 1-heterocyclic
(
1m and 1n), and 1-styryl (1o−q) groups with good yields and
regioselectivity. To the best of our knowledge, this protocol can
be considered as the first example of remote C5−H bond
activation for imidazo[1,5-a]pyridine, compared with the
6
reported Pd-catalyzed C3 and C1 arylation.
To further demonstrate its catalytic utility, we expanded the
scope of this Ni−Al bimetallic protocol to other alkyne
derivatives (Table 4). Good yields with high C5 selectivity
a
Table 4. C5-Alkenylation of 1a with Various Alkynes
a
Reaction conditions: 1 (0.50 mmol), 5 (0.60 mmol), Ni(cod) (5
2
mol %), IMes (20 mol %), and AlMe (60 mol %) in toluene (2 mL)
3
b
c
at 130 °C for 18 h. Isolated yield. Run with Ni(cod) (10 mol %),
IPr (20 mol %), AlMe (30 mol %), and 5 (1.5 equiv).
2
3
1
b
c
,
d
d
entry
2: R , R2
yield % (C3:C5) major r.r. (C5) E/Z (4)
position of styrene to afford 1,1-diaryl ethane adducts (7).
Likewise, a high level of C5-regioselectivity and yields were
consistently observed with a myriad of styrenes bearing different
functional groups, except those with sterically hindered ortho-
methyl (5c) and strong electron-withdrawing fluoro groups (5f)
1
2
2a: nPr, nPr,
2b: Et, Et
98 (1:10)
90 (1:10)
53 (1:3)
83 (1:16)
93 (1:11)
96 (1:8)
98 (1:8)
82 (1:20)
4aa
4ab
4ac
4ad
4ae
4af
99:1
96:4
e
3
2c: Ph, Ph
87:13
99:1
4
5
2d: Me, iPr
2e: Me, tBu
2f: Ph, tBu
2g: nBu, TMS
2h: Ph, TMS
91:9
99:1
99:1
99:1
99:1
(
entries 9−14). To our delight, such method canalso be extended
99:1
e
to other aliphatic olefinic reagents (5h,i) with high efficiency and
selectivity (entries 15−16). This simplified methodology of
affording linear C5-alkylated imidazo[1,5-a]pyridines like 7ai
would be a representative example to prepare the related
6
99:1
e
,
,
f
f
7
8
4ag
4ah
38:62
58:42
e
a
Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv), Ni(cod) (5 mol
), IMes (5 mol %), and AlMe (60 mol %) in toluene (2 mL) at rt
for 6 h. Isolated yield. Regioisomeric ratio. Determined by H
NMR. Run with IMes (20 mol %) at 130 °C. Run with 2 (1.05
2
biological active compounds like thromboxane A synthetase
%
2
3
14
b
c
d
1
inhibitor.
e
f
To gain insights into the reaction mechanism, the following
equiv).
experiments were conducted. Reaction of 1a-d with 2a was
2
examined in the presence and absence of AlMe . As revealed by
3
1
were observed in symmetrical alkynes 2a and 2b, but the addition
across diphenylacetylene (2c) was sluggish with favorable
regioselectivity for C5 (entry 3). Unsymmetrical dialkyl-alkynes
like 2d, 2e, and phenylalkyl-alkyne 2f (entries 4−6) proved to be
competent alkynes for this reaction with high yields and superior
C5 selectivity. Alkynes bearing a trimethylsilyl group (2g−h)
proceeded efficiently at a higher temperature (130 °C) to afford
H NMR analysis, the cleaved deuterium was inserted into 2a in
syn manner to give 3aa-d and 4aa-d , respectively (eqs 1 and 2,
Scheme S1). The kinetic isotope effect (KIE) was investigated
2
2
13
by an intermolecular competition between 1a and 1a-d . A
2
notable KIE value of 3.8 obtained in C3-alkenylation suggested
C−H bond cleavage may be significant with respect to the rate-
determining step (eq 3). Intriguingly, a KIE value of 1.1 was
observed in C5-alkenylation (eq 4), illustrating that C−H bond
cleavage was fast. These labeling results indicated C3- and C5-
alkenylation involved two different operating mechanistic
pathways. Further studies are necessary to investigate the
mechanistic details.
In summary, without resorting to directing group installment
on the substrate, we have disclosed a novel regiodivergent C−H
bond functionalization of imidazo[1,5-a]pyridine and deriva-
tives. The catalytic method features a cooperative interaction
between Ni and Al to invoke remote C−H activation via
alkenylation at the C5 position of imidazo[1,5-a]pyridine, which
4
ag and 4ah adducts with high C5 regioselectivity. Nevertheless,
formation of E and Z stereoisomeric mixtures was observed due
9b
to a facile self-isomerization process. In general, reactions of
unsymmetrical alkynes were highly selective to give the
corresponding adducts bearing a smaller substituent on the
same side with imidazopyridine (entries 4−8). Finally, we were
pleased to witness that excluding AlMe additive in the catalytic
3
13
reaction would switch the selectivity back to the C3 position.
Encouraged by the successful C5−H activation manifold, we
were curious whether the viability of this manifold could be
applied to styrenes and different olefinic substrates other than
alkynes. Positively, hydroheteroarylation of styrenes occurred
selectively at C5 position with various imidazo[1,5-a]pyridines in
good to moderate yields (entries 1−8, Table 5). Generally, the
addition of imidazo[1,5-a]pyridine occurred exclusively at α-
is unprecedented. Exclusion of AlMe cocatalyst switches the
3
reaction to the C3 site. Ongoing work seeks to gain a detailed
mechanistic understanding of the synergism offered by Ni−Al
bimetallic catalysis. Such mechanistic insights will be crucial for
C
dx.doi.org/10.1021/ol502314p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
developing bimetallic catalysis on the scope of the reaction in the
future. In addition, the possibilities to functionalize the C8
position of imidazo[1,5-a]pyridine are currently under explora-
tion in our laboratory.
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AUTHOR INFORMATION
Corresponding Author
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Lett. 2012, 14, 226−229. (k) Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-
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The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
This work is financially supported by National Science Council of
Taiwan (NSC-101-2628-M-001-002-MY3 grant) and Academia
Sinica Funding. This paper is also dedicated to the memory of
Lean-Seong Ong.
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