Diboron-assisted palladium-catalyzed transfer hydrogenation of N-heteroaromatics with water as hydrogen donor and solvent

Article abstract of DOI:10.1021/acs.orglett.6b01999

A Pd-catalyzed transfer hydrogenation of various N-heteroaromatic compounds with B₂pin₂ as a mediator and environmentally benign water as both solvent and hydrogen donor has been disclosed. This reaction proceeded under ambient temperature with a broad range of N-heteroaromatic compounds among which imidazo[1,2-a]pyridine derivatives were for the first time selectively reduced to 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines, which are the core structural motifs of an inhibitor of human O-GlcNAcase. Mechanistic studies suggested that the new protons in products are from water and Pd-H might be the key intermediate with B₂pin₂ as the H₂O activator.

Full text of DOI:10.1021/acs.orglett.6b01999

Letter
pubs.acs.org/OrgLett
Diboron-Assisted Palladium-Catalyzed Transfer Hydrogenation of
N‑Heteroaromatics with Water as Hydrogen Donor and Solvent
Qingqing Xuan† and Qiuling Song*,†,‡
†Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Boulevard,
Xiamen, Fujian 361021, P. R. China
‡National Laboratory for Molecular Sciences, Institute of Chemistry, CAS, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed transfer hydrogenation of
various N-heteroaromatic compounds with B2pin2 as a
mediator and environmentally benign water as both solvent
and hydrogen donor has been disclosed. This reaction
proceeded under ambient temperature with a broad range of
N-heteroaromatic compounds among which imidazo[1,2-
a]pyridine derivatives were for the first time selectively
reduced to 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines, which
are the core structural motifs of an inhibitor of human O-GlcNAcase. Mechanistic studies suggested that the new protons in
products are from water and Pd−H might be the key intermediate with B2pin2 as the H2O activator.
ince the first transfer hydrogenation (TH) of carbonyl
reduction of N-heteroaromatics. However, transition-metal-
Scompounds, known as Meerwein−Ponndorf−Verley catalyzed TH of N-heteroaromatics with H2O as both solvent
and hydrogen source has not yet been reported; at the same
time, few of the known methods could readily obtain
deuterium-labeled N-heterocycles with high D-incorportion.
B2pin2, which is air stable and inexpensive, has been
frequently used as a borylation reagent.7 Our group is devoted
to exploring the new reactivities of B2pin2 and has found that
α,β-unsaturated ketones can be selectively reduced in the
presence of unconjugated C−C unsaturated bonds with Cu/
B2pin2 system via a domino−borylation−protodeboronation
(DBP) strategy with water as the H-donor.8 Very recently, we
successfully converted arylacetylenes into β-phenylethyl
boronates with B2pin2 under transition-metal-free basic
conditions, once again, via DBP strategy.9 These two results
inspired us, and we envisioned that B2pin2 might assist the
reduction of N-heteroaromatic compounds by transferring the
hydrogen/deuterium from H2O/D2O to the substrates via DBP
strategy. As part of our ongoing interest in the new reactivity of
diboron reagent, we report herein an expedient pathway for the
hydrogenations of N-heteroaromatic compounds by employing
H2O as both solvent and hydrogen source at ambient
temperature (Scheme 1).
(MPV) reduction, was published in 1925, various homoge-
neous and heterogeneous transition-metal catalysts and
organocatalysts catalyzed by TH have been successfully
developed.1 However, the “sacrificial” hydrogen sources are
limited to alcohols, formic acid, Hantzsch esters, hydrazine,
alkanes, and cyclohexene, etc.2 As the most abundant,
environmentally benign, and inexpensive hydrogen-containing
source in the world, H2O would be an ideal hydrogen donor in
TH. There is another obvious advantage in the method with
water as H donor over other hydrogen sources: deuterium
could be easily incorporated into the final products to access D-
labeled compounds, which, as we know, are very important
materials in pharmaceuticals and life science since D2O is the
most readily accessible deuterium source. However, surpris-
ingly, there are only two elegant methods reported with H2O as
H-donor in TH to date: in 2007, Oltra reported hydrogen/
deuterium transfer from H2O/D2O to alkenes/alkynes,
mediated by Cp2TiCl with various late transition metals as
cocatalysts.3 Very recently, Stokes developed a Pd/C-catalyzed
hydrogen/deuterium transfer from H2O/D2O to alkenes/
alkynes with B2(OH)4 as an additive.4 However, in the above
two methods, organic solvents were always required to increase
the solubility of the substrates in order to reach high reactivity
of the transformations. If water could be served as both solvent
and H-donor in TH, it would be even more ideal and desirable.
Saturated and partially saturated N-heterocycles play
important roles as biologically active building blocks and key
intermediates in organic synthesis.5 Hydrogenation of N-
heteroaromatic compounds are one of the most important
strategies to access these two types of N-contained com-
pounds.6 Many valuable methods had been developed on the
To initiate the study, quinoline (1a) was chosen as a model
substrate. At first, CuBr in company with Cs2CO3 was chosen
as catalyst; in the presence of 2 equiv of B2pin2, the reaction
only gave the hydrogenation product 2a in 18% yield (Table 1,
entry 1). When Pd(OAc)2 was used in place of CuBr, the
loading of B2pin2 was increased to 3 equiv and the yield of 2a
was improved to 62% (Table 1, entry 3). To our delight, when
Received: July 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01999
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Our Approach on Transfer Hydrogenation of N-
Heteroaromatics
Scheme 2. Hydrogenation of Quinoline- and Quinoxaline-
Derived Substrates
a
a
Table 1. Reaction Optimization
b
temp
(°C)
yield
(%)
entry
metal
CuBr
base (x equiv)
solvent
CH3CN
c
1
Cs2CO3 (2)
Cs2CO3(2)
Cs2CO3(2)
Cs2CO3(2)
Cs2CO3 (2)
60
60
60
60
60
18
42
c
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CH3CN
CH3CN
CH3CN
3
62
d
4
<10
95
5
6
CH3CN/H2O
(1:1)
Pd(OAc)2
Cs2CO3(0.5) CH3CN/H2O
(1:1)
60
93
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs2CO3(0.5) H2O
Cs2CO3(0.5) H2O
H2O
60
rt
rt
rt
rt
rt
94
94
8
9
95
10
Cs2CO3(0.5) H2O
H2O
42
e
11
Pd(OAc)2
Pd(OAc)2
trace
92
f
a
12
H2O
All reactions were carried out with 1 (0.2 mmol), and isolated yields
a
are reported.
General procedure: 1a (0.2 mmol), B2pin2 (0.6 mmol), solvent (2
b
c
d
mL), under N2. Isolated yield. B2pin2 (0.4 mmol). PPh3 (0.04
mmol) was used. Under air. B2pin2 was replaced with B2(OH)4 (0.6
mmol).
e
f
could afford the desired products in good to excellent yields
under conditions A (Table 1, entry 9) and B (Table 1, entry 8).
The electronic effects of the substituents on the aromatic ring
affected the hydrogenation largely under conditions A (Scheme
2, 2f). We think that the substrates/products might act as bases
and ligands, which could assist the transmetalation process of
B2pin2. When strong electron-withdrawing groups were
present, the basicity of the substrates/products declined and
the reaction required extra base. It is noteworthy that 2h and 2i,
which were isolated from the trunk bark of the South American
tree Galipea officinalis and showed antimalarial activity, could
be successfully accessed under our reaction conditions.5
Luckily, some polycyclic aromatic compounds could react
smoothly, offering the hydrogenated products in good yields
(Scheme 2, 2j−l). It is worth mentioning that 2l, which could
be obtained from phenanthridine, can act as the substitute for
Hantzsch esters.10 Tetrahydroquinoxalines are very useful
moieties and present in a wide range of biologically and
medicinally active compounds.11 We were glad to discover that
quinoxalines could be smoothly hydrogenated under our
conditions and afforded tetrahydroquinoxalines in high yields
(Scheme 2, 2m−o).
Although hydrogenation of quinoline- and quinoxaline-
derived substrates has been widely reported,12 the TH of
imidazo[1,2-a]pyridines were barely known despite the
importance of these compounds in pharmaceutical and
synthetic organic chemistry. Delightfully, some imidazo[1,2-
a]pyridines smoothly underwent a hydrogenation process to
afford 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines in excellent
yields under our reaction conditions (Scheme 3). We
discovered that this reaction process showed an “on-water”
the solvent was changed to CH3CN/H2O (1:1), the reaction
proceeded smoothly, affording 2a in 95% yield. Next, we
attempted to study the effects of the amount of Cs2CO3 and
the temperature. Seemingly, the amount of Cs2CO3 had no
impact on the hydrogenation of 1a, and the reaction proceeded
well in water, even at room temperature, to give 2a in 94−95%
yield (Table 1, entries 8 and 9, conditions B and A). However,
when the reaction was carried out in the presence of Cs2CO3
alone, it could also give 2a in 42% yield (Table 1, entry 10). It
seemed that the reaction mechanism might be different from
what we envisioned (entry 9 vs entry 10). In the later research
of substrate scope, we found that some substrates can only
afford satisfied results in the presence of both Pd(OAc)2 and
Cs2CO3 (Scheme 2). The result indicated that base, which
would promote the transmetalation process of B2pin2, indeed
had some equivocal effects on our reactions. Air was
detrimental to the hydrogenation reaction (Table 1, entry
11), which suggested that an air-sensitive intermediate might be
formed in the reaction process. Other metal salts were also
screened, but none of them afforded results as satisfying as
Pd(OAc)2 did (Supporting Information). B2(OH)4, which has a
bad smell and is more expensive than B2pin2, could also give 2a
in 92% yield (Table 1, entry 12).
Subsequently, the optimized conditions were used for further
evaluation of the substrate scope (Scheme 2). Various
quinoline-derived substrates were subjected to the hydro-
genation reactions and smoothly converted into 1,2,3,4-
tetrahydroquinolines. The substituents at the 2,4-positions of
the quinolines slightly influenced the yields; however, they both
B
DOI: 10.1021/acs.orglett.6b01999
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Hydrogenation of Imidazo[1,2-a]pyridine-
Derived Substrates
Scheme 4. Large Scale Synthesis of anti-Trypanosomal 4
a
Scheme 5. Deuterium-Labeled Experiments
a
All reactions were carried out with 1 (0.2 mmol) and the reported
yields were isolated.
when H2O was replaced by D2O under the standard conditions
A (eq 1). This result clearly demonstrated that water is the H-
donor for this hydrogenation reaction. When the reaction was
conducted with the mixture of H2O/D2O (1:1), interestingly,
only product 2a was obtained, and no deuterium was
incorporated into the final product at all (eq 2). This reaction
suggested that H atom transfer might be the rate-determing
step (rds) in the entire hydrogenation pathway, which is
consistent with the previous report.3
effect (Supporting Information). It is noteworthy that the
products 2p−t are important constitutional units of the
PUGNAc−imidazole hybrid, which is an inhibitor of human
O-GlcNAcase.13
Noteworthy and interestingly, other N-heteroaromatic
compounds could also afford useful products. For example, 5-
naphthyridine could selectively hydrogenate one pyridine ring
into compound 2u under conditions A (Figure 1), and
There are two possible pathways that could transfer H onto
the N-heteroaromatic compounds: the first one is domino−
borylation−protodeboronation (DBP) as we reported in our
previous studies.8,9 However, as far as we know, all
protodeboronation proceeded under basic or F− anion
conditions with elevated temperatures, and in some cases,
benzylic positions are critical for the success of protodeboro-
nation.16 In our transformation, conditions A are neutral, both
conditions were conducted at ambient temperature, and the
benzylic position is not always used. Therefore, we have reason
to believe that our transformation could not proceed via a DBP
process. The second pathway is via M−H insertion over N-
heteroaromatic compounds, in which M−H was formed in situ
via transfer hydrogenation from H2O to transition metal via the
assistance of a mediator; in our case, B2pin2 acts in that role.
On the basis of all of experiments as well as precedent
reports,3,4 we proposed a tentative mechanism which is shown
in Scheme 6: the reaction is initiated by transmetalation
between Pd(OAc)2 and B2pin2, leading to intermediate I in situ.
The intermediate I would readily form complex II with H2O,
which might facilitate the H atom transfer from H2O to
palladium, affording [Pd−H] species III. Then, quinoline
would coordinate with III to give complex IV, followed by 1,5-
hydride transfer to afford the intermediate V. Subsequently, the
hydrolysis of intermediate V gives enamine A and generated
[Pd]II, which then interacts with B2pin2 and H2O to regenerate
[Pd−H] species III and release HOBpin.17 The formed
enamine A is isomerized to imine B, which would coordinate
with III to give complex VI. Subsequent insertion of [Pd−H]
to the CN bond forms intermediate VII. Finally, the 1,2,3,4-
tetrahydroquinoline is released via hydrolysis with H2O as the
H-donor.
Figure 1. Hydrogenation of other N-heteroaromatics under conditions
A.
Figure 2. Structure of topoisomerase I inhibitor 3.
compound 2u is a core unit of compound 3 (Figure 2),
which is proven to be able to inhibit topoisomerase I activity.14
It needs to be pointed out that pyridine with electron-
withdrawing CO2Et at the 3-position could be only partially
hydrogenated to afford compound 2v under conditions A.15
A large-scale experiment was also carried out with 2-
methylquinoline (1b) under conditions A, and it offered the
desired product 2b in 85% yield. Followed by sulfonylation,
compound 4, which showed antitrypanosomal activity,5 could
be readily obtained in 80% yield (Scheme 4).
In order to understand the origin of hydrogen in the
transformations, deuterium-labeled experiments were carried
out with 1a under various conditions (Scheme 5). Trideu-
terated 5 was obtained with very high deuterium incorporation
In conclusion, we successfully developed a novel Pd-
catalyzed transfer hydrogenation of various N-heteroaromatic
C
DOI: 10.1021/acs.orglett.6b01999
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Plausible Mechanisms
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compounds with B2pin2 as mediator and H2O as both solvent
and H-donor at ambient temperature. A myriad of N-
heteroaromatic compounds could be selectively reduced with
a broad functional groups tolerance in good to excellent yields.
For the first time, imidazo[1,2-a]pyridine derivatives have been
successfully reduced with good chemoselectivity rendering
5,6,7,8-tetrahydroimidazo[1,2-a]pyridines which are the core
structure of an inhibitor of human O-GlcNAcase. This reaction
could be easily scaled up without loss of its efficiency. Broad
substrates scope, mild reaction conditions, environmentally
benign H-donor, and simple operations feature the reaction and
make it an alternative way to the existing TH methods. Further
studies on the detailed mechanism and applications on other
systems with this novel catalytic system will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01999.
Procedures, characterization, and spectral data (PDF)
(16) (a) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J.
Am. Chem. Soc. 2010, 132, 17096. (b) Hong, K.; Liu, X.; Morken, J. P.
J. Am. Chem. Soc. 2014, 136, 10581.
AUTHOR INFORMATION
Corresponding Author
■
(17) HOBpin was detected by 11B NMR spectra in the crude reaction
mixture using conditions A. See the Supporting Information for details.
*E-mail: qsong@hqu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21202049), the Recruitment Program
of Global Experts (1000 Talents Plan), the Natural Science
Foundation of Fujian Province (2016J01064), and Fujian
Hundred Talents Plan and Program of Innovative Research
Team of Huaqiao University (Z14X0047) are gratefully
acknowledged. We also thank the Instrumental Analysis Center
of Huaqiao University for analysis support.
D
DOI: 10.1021/acs.orglett.6b01999
Org. Lett. XXXX, XXX, XXX−XXX