Umpolung of protons from H2O: A metal-free chemoselective reduction of carbonyl compounds: Via B2pin2/H2O systems

Article abstract of DOI:10.1039/c7ob00820a

H₂O is routinely described as a proton donor, however, in the presence of diboron compounds, the umpolung reaction of H₂O under metal-free conditions was successfully developed, which could afford hydride species, leading to a highly efficient and chemoselective reduction of CO bonds. This strategy exhibits excellent chemoselectivities toward carbonyl groups in the presence of ester, olefin, halogen, thioether, sulfonyl, cyano as well as heteroaromatic groups.

Full text of DOI:10.1039/c7ob00820a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00820A
Organic & Biomolecular Chemistry
ARTICLE
Umpolung of Proton from H2O: A Metal-free Chemoselective
Reduction of Carbonyl Compounds via B2pin2/H2O Systems
Qingqing Xuan,a Cong Zhaoa and Qiuling Songb
Received 00th January 20xx,
Accepted 00th January 20xx
H2O is routinely described as proton donor, however, in the presence of diboron compounds, the successful umpolung
reaction of H2O under metal-free conditions was developed, which could afford hydride species, leading to a highly
efficient and chemoselective reduction of C=O bonds. This strategy exhibits excellent chemoselectivities toward carbonyl
group in the presence of ester, olefin, halogen, thioether, sulfonyl, cyano as well as heteroaromatic groups.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Presumably, if the polarity of proton from H2O could be
inverted (Figure 1B), just like umpolung reactions of carbonyls7
and imines,8 it would afford hydride species and create new
opportunities for the efficient hydrogenation reactions from
the most abundant and greenest H source on the earth.
Introduction
Diboron compounds have been extensively explored in the
past few decades, and these compounds now feature
prominently in both metal-catalyzed and metal-free
methodologies for the formation of B−C bonds.1 However, as
good deoxygenating reagents, the “reductive” property of
diboron compounds has been far underdeveloped and
underestimated.2 Very recently, Stokes reported that B2(OH)4
could efficiently mediate the transfer of H or D atoms from
water directly onto unsaturated C−C bonds using a palladium
catalyst with CH2Cl2 as solvent.3 Almost at the same time, we
found that diboron compounds could chemoselectively
promote the reductions of N-heteroaromatics under ambient
temperature via transfer hydrogenation with water as both
solvent and H donor.4 Soon after, Prabhu and coworkers
disclosed that H2 was generated from H2O in the presence of
Figure 1. Natural and Inverted Polarity of H-atom of H2O
The reduction of carbonyl compounds to alcohols is one of
important processes for the synthesis of chemicals that are
vital to our daily life. However, the catalysts that facilitate
these reactions are predominantly based on rare, expensive,
and often toxic transition metals.9 Consequently there exists a
strong incentive for chemists to develop new systems based
on transition metal-free conditions.10 In 2014, Du and
coworkers reported a highly enantioselective H2 involved
synthesis of alcohols via FLPs (frustrated Lewis pairs) strategy
from silyl enol ethers rather than ketones, as C=O bonds are
more thermodynamically inert (Scheme 1A).11 However, soon
after, Douglas and Andrew independently reported the direct
hydrogenation of C=O bonds still based on the concept of FLPs,
B2pin2 in toluene and C=C bonds, CC bonds were reduced
smoothly.5 These reports suggest that in the system of
B2pin2/H2O, H2O may act as hydrogen source in transfer
hydrogenations (TH). Although alcohols, formic acid, Hantzsch
esters, hydrazine had been widely employed in TH,6 H2O was
scarely used. With our ongoing pursuit of the new reactivities
of diboron compounds, we, herein, would like report a highly
chemoselective reduction of C=O bonds based on the
umpolung reaction of proton from H2O in B2pin2/H2O systems.
H2O, which is one of the most abundant molecules in the
world, contains incredible capabilities and is the most
important matter for living animals and plants. However, due
to the intrinsic electronic difference between H and O atoms,
H2O is usually considered as a proton donor (Figure 1A).
a.Address here.
b.Address here.
c. Address here.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Metal-free Hydrogenation of C=O Bonds
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under totally metal-free conditions under H2 atmosphere in over Cs2CO3 (Table 1, entry 9 vs entry 8), therefore DBU was
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ether (Scheme 1B).12 Herein, we’d like to report our progress chosen as the optimal base under our conditions. And with no
DOI: 10.1039/C7OB00820A
on the non-metal catalyzed hydrogenation of carbonyl surprise, the yield was decreased dramatically with catalytic
compounds mediated by diboron reagents with water as amount of DBU (Table 1, entry 10-11).
hydride source as well as solvent (Scheme 1C).
Gratifyingly, this metal-free catalytic systems were
demonstrated to be highly effective and chemoselective
toward the reduction of ketones (Scheme 2). Aryl ketones with
either electron-donating or electron-withdrawing substituents
on the benzene ring were all well tolerated under this reaction
Results and discussion
Our initial studies were carried out by examining the reduction
(
2a-2i). When more electron deficient ketone, such as
of acetophenone (1a) under the standard conditions reported
by our previous work (Table 1, entry 1).4 Acetophenone (1a
)
trifluoroacetophenone 1j was used, the desired product was
obtained in higher yield (2j). 1-Indanones (1l-1m), 1-tetralone
was converted completely, affording the desired alcohol 2a as
well as unexpected 3a in quantitative yield. After purification
through silica gel chromatography, the B-O bond of 3a was
(1n) and 9-fluorenone (1o) were also effective substrates to
give the desired product in 65-87% yields (2l 2o). In addition,
-
protonated and completely converted to 2a 13
. The ratio of 2a
alkyl ketones underwent the reductive process smoothly, and
afforded the corresponding alcohols in high yields (2p-2r). This
catalytic system exhibited excellent chemoselectivity toward
C=O bonds in the presence of ester and cyano groups as well
as sulphone group (2g, 2s-2w). Ester groups were very inert
functional group, and they could be retained even in the
presence of Pd(OAc)2.
and 3a was also determined by GC-MS. However, when more
active diboron compound, B2(Cat)2, was employed, it gave
messy results (Table 1, entry 2). Comparingly, when more inert
B2(OH)2 was used, only trace amount of product was detected
(Table 1, entry 3). The necessity of metal and base was also
examined (Table 1, entry 4-5). Surprisingly, Pd(OAc)2 was
unnecessary; on the contrary, base was indispensible in our
systems and it was found that the desired product was
obtained in 51% yield in the presence of Cs2CO3 (0.5 equiv)
alone. Thus, the metal-free mechanism might be quite
different from the aforementioned [Pd-H] intermediate, which
is sensitive to air. In order to prove our hypothesis, this metal-
free reaction was conducted under air, to our delight, the
desired product was obtained in 52% yield (Table 1, entry 6),
which clearly demonstrated that this reaction undertakes a
totally different pathway from our previous report. Next, the
amount of base and temperature were furtherly investigated
(Table 1, entry 7-8). It suggested that chemical equivelent of
base was necessary and excellent yield was obtained at 60 oC.
Table 1. Reaction Optimizationa
Base
(equiv)
Pd(OAc)2 Cs2CO3 (0.5)
B-
Yield
Ratio
Entry
1c
2 c
3 c
4 c
Metal
source (2a+3a)(%)b (2a/3a)(%)b
B2pin2
quantitative
complex
trace
trace
51%
63/37
-
Pd(OAc)2 Cs2CO3 (0.5) B2(Cat)2
Pd(OAc)2 Cs2CO3 (0.5) B2(OH)4
-
Pd(OAc)2
B2pin2
B2pin2
B2pin2
B2pin2
B2pin2
B2pin2
B2pin2
B2pin2
-
5 c
-
-
-
-
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
DBU (1.0)
78/22
81/19
80/20
85/15
86/14
ND e
ND e
6
52%
7
78%
8 d
9 d
10d
11d
95%
aAll reactions were carried out with 1 (0.2 mmol), and isolated
yields are reported.
Scheme 2. Metal-free Chemoselective Hydrogenaton of Ketones
98%
DBU (0.5)
71%
DBU (0.2)
25%
In fact, the reduction ability of B2pin2/H2O systems can be fine
controlled through the addition of Pd(OAc)2 or not (Scheme 3).
a General procedure: 1a (0.2 mmol), B-source (0.24 mmol), H2O (2 ml),
b
c
under air. Determined by GC-MS. The reaction was carried out For instance, ethyl quinoline-6-carboxylate (
4
) and ethyl
under N2. d The reaction was carried out at 60 oC .eNot detected.
In addition, organic base, such as DBU was tested in our
reaction systems as well, and it showed superior reactivity
nicotinate (
6) could be selectively hydrogenated on
N-heterocycles in the presence of Pd(OAc)2 under B2pin2/H2O
systems(under our previous condition B) 4, while ester groups
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were kept untouched.1 In addition, benzonitrile (
ARTICLE
5
) could also rings in our previous report; however, under thVisiewmAertitcalel-Ofnrleinee
underwent the hydrogenation process smoothly, delivering condition, the heteroaromatic rings waDsOrIe: t1a0i.1n0e3d9,/Cw7OhBil0e08C2=0OA
benzylamine (
8
) under the above conditions.14 Thus, compared bond was smoothly hydrogenated to afford product 2ae
.
with our current standard conditions, obviously, the reductive
ability was increased when Pd(OAc)2 was presented since
cyano group was intact under our current standard condition
yet it was reduced with Pd(OAc)2 as catalyst. So, it’s deemed
that there would be great potential of B2pin2/H2O systems to
be developed.
In order to understand the origin of hydrogen, deuterium-
labeled experiments were carried out with 1a under standard
conditions (Scheme 5). Deuterated product
4 was obtained
with high deuterium incorporation (>90%) when the reaction
was performed in absolute D2O (eq 1). 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 from polymer A to C=O bounds
might be the rate-determing step (rds) in the entire process
(Scheme 6), and it could not be a hydrogen gas involved
reaction, which is consistent with our previous report as well
as precedent literature.
Scheme
3. Chemoselective Hydrogenation on Various Functional Groups under Pd(OAc)2, B2pin2,
Cs2CO3 in Water.
Chemoselective hydrogenation of unsaturated carbonyl
compounds while maintaining the C=C bonds is an important
class of reactions, because the corresponding unsaturated
alcohols often serve as valuable intermediates in fragrances as
well as pharmaceuticals.15 However, these transformations are
challenging, since the hydrogenation of C=O bond is
thermodynamically and kinetically unfavored.16 Several
heterogeneous catalysts (metal nanoparticles supported on
metal oxides) have been reported effectively to realize this
transformation, as the metal oxides can serve as Lewis acid
centre which might activate C=O bonds.17 In our reaction
systems, B2pin2 not only acted as deoxygenating reagent, but
also served as Lewis acid. Thus, geraniol (2x), myrac alcohol
Scheme 5. Deuterium-Labeled Experiments
To figure out the B species which were existed during our
transformation, the reaction was monitored by 11B NMR
spectroscopy (Figure 2). As we can see, the peak of starting
material B2pin2, which showed at about 31.2 ppm, gradually
diminished in our reaction process and a new peak showed at
about 22.7 ppm, which was identical with the pinBOBpin, and
became stronger along with the reaction going.
(2y) and citronellol (2z) could be successfully afforded from the
corresponding aldehydes (Scheme 4). In addition,
heteroaromatic aldehydes could undergo hydrogenation
smoothly on the C=O bonds under the standard conditions,
while the hetero-aromaticity was well kept (2aa
-2ae). It’s
worth to mention that N-heterocycles constructed pyridine-
Figure 2 11B NMR Spectra of reaction process
Diborylation (type I) and monoborylation (type II) of C=O
bonds had been achieved under the catalyst of copper (I) and
base, which were deemed processing via copper(I) boryl
complex.18 Noteworthily, the two types of boronates were
reported to be stable in water system18a, and deboronation
could not be easily occured even under basic conditions
(heating is usually required to achieve the proton
deboronation process whilst our reactions were proceeded
under ambient temperature).2c, 19 Under our systems, first of
aAll reactions were carried out with 1 (0.2 mmol), and isolated
yields are reported.
Scheme 4. Metal-free Chemoselective Hydrogenaton of Aldehydes with Various Unsaturated Systems.
all , type
I
and type II products were not deteced by GC-MS in
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the crude reaction mixtures, secondly, 11B NMR experiment for ethyl acetate, repeat three times. The combined organic layer was
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DOI: 10.1039/C7OB00820A
the entire reaction process (see Figure 2) also supported our evaporated under reduced pressure, and the product was purified
observation in which only B2pin2 and pinBOBpin peaks showed by column chromatography.
up in the spectra and no other type of 11B NMR was detected;
presumably, if type I or type II products were generated in the
Conclusions
In conclusion,
hydrogenation of C=O bonds mediated by B2pin2 via umpolung
of H2O was disclosed. It is the first report that H2O could serve
as hydride donor activated by diboron reagent under metal-
reaction, they are stale in the reaction and could be either
detected by GC-MS or observed by 11B NMR. Based on the
observations and analysis, we have reasons to believe that the
Domino-Borylation-Protodeboronation (DBP) process did not
occur in our system and thus it could be excluded.
a
novel and highly chemoselective
free
conditions.
This
strategy
exhibits
excellent
chemoselectivity on carbonyl group in the existence of halogen,
ester, olefin, sulfonyl, thioether, cyano and heteroaromatic
groups. The proposed mechanism suggested that diboron
reagent might act as both activator of water as well as Lewis
acid for activation of C=O group, which might explain the high
chemoselectivity of this method. Enantioselective version of
this transformation as well as further synthetic utility and
detailed mechanism study is under the way in our laboratory.
Figure 3 Diborylation and Monoborylation Products C=O bonds
Based on all the results of our experiments, we proposed the
following mechanism (Scheme 6). B-B bond, which was
polarized in the presence of base, could chelate with H2O,
forming species
somewhat similar to solvation effect. In thes pecies
A
under the electronic field effect, which was
, the O-
A
atom of H2O was inserted into the polarized B-B bond, forcing
H-atom to leave as a hydride species. Then, C=O bond was
attacked by the hydride, followed by hydrolysis, affording the
Acknowledgements
The acknowledgements come at the end of an article after the
conclusions and before the notes and references.
corresponding alcohols
was also detected by GC-MS. It’s deemed that, C=O bond
would chelate with the polarized B-B bond to form species
when attacked by the newly generated hydride, it gave
compounds . In this process, diboron compounds acted as
2. In our reaction system, compound C
B,
Notes and references
C
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Lewis acid, which could activate C=O bonds. This result might
be the explanation for the selective hydrogenation of C=O
bonds, even in the presence of conjugated C=C bonds.
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the corresponding alcohol when purified through silica gel
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C was unstable, it would be hydrolyzed to
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Scheme 6. Proposed Mechanism
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Experimental
To a reaction tube equipped with a stir bar, 76.2 mg of B2pin2 (0.3
mmol) and base (0.02 mmol) were added. Next, 24.0mg (0.2 mmol)
of acetophenone (1a) and H2O (2ml) was added via syringe, then
sealed the reaction tube. The mixture was stired at 60oC for about
10h. After the reaction was finished, the mixture was extracted with
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