Tetrahydroxydiboron-Mediated Palladium-Catalyzed Transfer Hydrogenation and Deuteriation of Alkenes and Alkynes Using Water as the Stoichiometric H or D Atom Donor

Article abstract of DOI:10.1021/jacs.6b02132

There are few examples of catalytic transfer hydrogenations of simple alkenes and alkynes that use water as a stoichiometric H or D atom donor. We have found that diboron reagents efficiently mediate the transfer of H or D atoms from water directly onto unsaturated C-C bonds using a palladium catalyst. This reaction is conducted on a broad variety of alkenes and alkynes at ambient temperature, and boric acid is the sole byproduct. Mechanistic experiments suggest that this reaction is made possible by a hydrogen atom transfer from water that generates a Pd-hydride intermediate. Importantly, complete deuterium incorporation from stoichiometric D₂O has also been achieved.

Full text of DOI:10.1021/jacs.6b02132

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Communication
Tetrahydroxydiboron-Mediated Palladium-Catalyzed Transfer
Hydrogenation and Deuteriation of Alkenes and Alkynes
Using Water as the Stoichiometric H or D Atom Donor
Steven P. Cummings, Thanh N. Le, Gilberto Enrique
Fernandez, Lorenzo G. Quiambao, and Benjamin J. Stokes
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02132 • Publication Date (Web): 02 May 2016
Downloaded from http://pubs.acs.org on May 4, 2016
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Tetrahydroxydiboron-Mediated Palladium-Catalyzed Transfer Hy-
drogenation and Deuteriation of Alkenes and Alkynes Using Water
as the Stoichiometric H or D Atom Donor
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Steven P. Cummings, Thanh-Ngoc Le, Gilberto E. Fernandez, Lorenzo G. Quiambao, and Ben-
jamin J. Stokes*
School of Natural Sciences, University of California, Merced, 5200 N. Lake Road, Merced, CA 95343, USA
Supporting Information Placeholder
from D2O. We envisioned developing a complementary
approach to metal hydride generation from water by har-
hydrogenations of simple alkenes and alkynes that use
ABSTRACT: There are few examples of catalytic transfer
nessing the versatility of B2X4 reagents, which can serve as
both a transition metal oxidant and as a Lewis acid to
engage water.
water as a stoichiometric H or D atom donor. We have
found that diboron reagents efficiently mediate the trans-
fer of H or D atoms from water directly onto unsaturated
C–C bonds using a palladium catalyst. This reaction is
conducted on a broad variety of alkenes and alkynes at
ambient temperature, and boric acid is the sole byprod-
uct. Mechanistic experiments suggest that this reaction is
made possible by a rate-determining H atom transfer
event that generates a Pd–hydride intermediate. Im-
portantly, complete deuterium incorporation from stoi-
chiometric D2O has also been achieved.
Tetrahydroxydiboron, which is infrequently used for
non-borylative purposes,6 was envisioned as the ideal di-
boron reagent to transfer H atoms from water across un-
saturated carbon-carbon
Scheme 1. The Use of Water as the H Atom Donor in
Catalytic Transfer Hydrogenations of Alkenes
The catalytic hydrogenation of alkenes or alkynes is
most often executed in batches by direct application of
hydrogen gas. Alternatively, transfer hydrogenation (TH)
appeals to many bench chemists because it does not re-
quire the use of a flammable gas. A wide variety of H or D
atom donors are available for use in both homo- and het-
erogeneous catalytic TH reactions,1 but there are few ex-
amples of TH reactions that use water stoichiometrically
to hydrogenate an unsaturated carbon-carbon bond2 de-
spite the safety and cost benefits associated with the use
of H2O and D2O. While stoichiometric TH of unactivated
alkenes and alkynes using H2O could be broadly useful for
reductions, the transfer deuteriation (TD) of alkenes and
alkynes using D2O is of special interest because deuteri-
um-labeled small molecules are useful for the study of
synthetic mechanistic pathways,3 for pharmacokinetic
studies towards drug discovery,4 and for preparing LC-MS
internal standards.5
bonds (Scheme 1B). Mechanistically, we hypothesized
that, following oxidative addition to give C,7 water could
coordinate to one boron atom to give adduct D (Scheme
1C). Then, H atom transfer could liberate boric acid to
afford Pd-hydride E.8 Migratory insertion of an unsaturat-
ed substrate, such as A, could afford Pd-alkyl intermedi-
ate F, which could coordinate another equivalent of water
(G) and generate Pd-hydride H following another H atom
transfer event. Reductive elimination from H could gen-
erate the second C–H bond, and afford B. Below, we de-
scribe the successful development of this concept into an
efficient hydrogenation and deuteriation reaction that
The only method we are aware of that uses a near-
stoichiometric amount of water as the putative H atom
donor relies on a single electron transfer from titanocene
chloride to activate the O–H bond for metal hydride gen-
eration (Scheme 1A).2 This reaction suffers from incon-
sistent yields and incomplete deuterium incorporation
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avoids the necessity of H2 or D2 gas and reduces a wide Pd(OAc)2 was also observed to catalyze the reaction (en-
try 8). Pt/C and Rh/C are also effective catalysts.13 As our
final piece of optimization, we probed the influence of the
electronic nature of the diboron reagent, and found that
the arene-stabilized bis(catecholato)diboron variant func-
tioned as effeciently as tetrahydroxydiboron (Table 1, en-
try 9). In contrast, bis(pinacolato)diboron afforded only
trace amounts of product (entry 10), underscoring the
importance of the electronic nature of the diboron rea-
gent.6a,14
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2
3
4
5
6
7
8
variety of alkenes and alkynes to alkanes quantitatively at
ambient temperature.9
We discovered that untreated palladium on carbon
(Pd/C) could quantitatively transfer hydrogen atoms from
water to 1,1-diphenylethylene 1a at ambient temperature
in dichloromethane in the presence of tetrahydroxydibo-
ron and just a slight excess (2.1 equivalents total, with one
equivalent required per B atom) of water (Table 1, entry 1).
This result suggests that H2 gas is not being generated by
B2(OH)4 hydrolysis in situ, as H2 would be likely to escape
from solution and lead to low yield if this were the case.
Alternatively, B2(OH)4 hydrolysis would lead to the in-
termediate H–B(OH)2, which could potentially hydrobo-
rate the alkene to give
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With optimized conditions in hand, we began exploring
the scope of alkenes that could be hydrogenated with
water, starting with terminal non-styrenyl alkenes (Table
2, 1b–1f). This group was hydrogenated in quantitative
yield in each case, and includes octene (1b), as well as
substrates bearing oxygen-containing functional groups,
such as primary alcohols (1c), benzyl ethers (1d), esters
(1e), and α,β-unsaturated ketones (1f). Disubstituted cy-
clic alkenes were readily hydrogenated, including aliphat-
ic (1g and 1h) and heterocyclic substrates (1i and 1j). In
contrast, 1-chlorocyclopetene (1k) afforded only a trace
amount of 2k, while
Table 1. Reaction Optimization
Table 2. Scope of The Hydrogenation of Alkenes
B2(OH)4 (1.1 equiv)
Pd/C (5 mol %)
R1
R2
R3
R4
R1
R2
R3
R4
+
H2O
(5 equiv)
CH2Cl2 (0.3 M)
rt, 5 h
1
2
terminal non-styrenyl alkenes
EtO2C
O
HO
1c, >95%a
BnO
n-Hex
3
3
Et
EtO2C
1e, 91%
1f, >95%a
1b, >95%a
1d, 97%
cyclic alkenes
C(OH)Me2
These reactions employed untreated catalysts unless other-
wise noted, and were conducted on 2.0 mmol scale. In all
Boc
O
N
a
cases, the substrate conversion matched the yield. Deter-
Cl
1g, >95%a 1h, >95%a 1i, >95%a 1j, 97%b 1k, tracea
1
Me
mined by H NMR analysis of reaction mixtures upon filtra-
1l, 69%a
(64% conv.) (75:25 trans:cis)
b
tion using 1,3,5-trimethoxybenzene as an internal standard.
c
Reduced Pd/C was used in this experiment. This reaction
acyclic polysubstituted alkenes
CO2Et
OH
OBn OTIPS
was conducted in the presence of 145 equivalents of Hg per
Pd.
Ph
Ph
Ph
Ph
1n, 21%a
(58% conv.)
1o, 90%a
1p, 95%
1m, 90%
Ph
alkyl boronic acids, but alkyl boronic acids do not prote-
odeboronate under our reaction conditions.10 No back-
ground hydrogenation occurred in dichloromethane in
the absence of water (entry 2), whereas hydrogenation did
occur in anhydrous MeOH (entry 3) and anhydrous THF
(entry 4) in the absence of added water. Turning our at-
tention to the catalyst itself, we found that a pre-reduced
form of Pd/C did not afford a detectable amount of prod-
uct (Table 1, entry 5), suggesting that the reaction may be
catalyzed by metal nanoparticles.11 The use of Pd(PPh3)4 as
catalyst also resulted in no substrate conversion, further
implicating catalytically active Pd nanoparticles, which
would be poisoned by phosphines (entry 6).7 As a final
piece of evidence in support of the nanoparticulate nature
of the catalyst, a mercury drop experiment was per-
formed, and resulted in a significant decrease in the con-
version of 1a (entry 7).12 In addition to untreated Pd/C,
(93% conv.)
t-Bu
Ph
Ph
Ph
Ph
Ph
1s, 95%
Ph
1q, 97%b
1a, 92%b
1r, 95%
CO2H
Ph
Ph
Ph
Ph
Ph
Me
Me
Ph
NHAc
1w, 88%a,d
(95% conv.)
Ph
Me
Me
Me
1t, 99%
1u, 88%a,c
1v, >95%a
(88% conv.)
styrenes
p-
CF3(C6H4)
1aa, 93%
p-
p-NO2(C6H4)
1ab, 38%a
(55% conv.)
C6H5
p-OMe(C6H4)
1y, 96%
Cl(C6H4)
1x, 96%
1z, 96%
Br
p-N3(C6H4)
1ac, 6%a
p-Br(C6H4)
1ad, 32%a
m-Br(C6H4)
o-
Br(C6H4)
C6H5
1ag, 0%a
(84% conv.) (66% conv.)
1ae, 51%a
(66% conv.)
1af, 25%a
(77% conv.) (82% conv.)
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Isolated yields are reported, and starting material was con-
We selected 3c as a model substrate for D atom incor-
poration from D2O. Subjection of 3c to our optimized
conditions using D2O instead of H2O resulted in only 48%
deuterium incorporation (Scheme 2A). We ascribe this
disparity to the exchange of the D atoms of water with the
H atoms of tetrahydroxydiboron. By using a substantial
excess of D2O (50 equivalents), 94% D incorporation was
observed. To achieve stoichiometric D atom incorpora-
tion from D2O, either B2(OD)4 or hydroxyl-free
bis(catecholato)diboron are required: 98% D atom incor-
poration was achieved using just 1.2 equivalents of water
per boron atom. These results are an improvement upon
the 74% D atom incorporation efficiency reported by
Oltra and co-workers.2 The apparent non-quantitative
deuterium incorporation could be ascribed to either ad-
ventitious water, or the exchange of aromatic H atoms via
Pd-π-benzyl isomerization.17
a
1
1
2
3
4
5
6
7
8
sumed in full, unless otherwise noted. Determined by H
NMR analysis of the crude reaction mixtures using 1,3,5-
b
trimethoxybenzene as an internal standard. 60 hour reac-
tion of 5.0 mmol of the indicated substrate using 0.5 mol %
c
d
Pd/C. Reaction time was 18 h. H2O was used as the sol-
vent.
(+)-terpineol 1l afforded reasonable product yield with
modest diastereoselectivity favoring the trans diastere-
omer.
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Most of the acyclic polysubstituted alkenes that we
evaluated (1m–1w) were cleanly converted to product,
with the exception of trans-cinnamyl alcohol (1n). In this
case, aldehyde byproducts predominate, likely due to Pd-
induced isomerization.13,15 Additionally, during reaction
monitoring of cis-stilbene 1r, isomerization to trans-
stilbene 1q was observed, suggesting a reversible H-atom
addition.13 Excellent yields were achieved for trisubstitut-
ed (1t and 1w) and even tetrasubstituted (1u and 1v) al-
kenes. Notably, acetamidocinnamic acid 1w was success-
fully hydrogenated in 88% yield using H2O as solvent.
Having achieved conditions for near-quantitative al-
kyne deuteriation using stoichiometric D2O, we sought to
apply our method to the deuteriation of unsaturated C–C
bonds comprised of inequivalent carbon atoms. Using 1,1-
diphenylethylene 1a as substrate, we observed the ex-
pected net incorporation of one deuterium atom per alkyl
carbon atom of the starting alkene, but the deuterium
atoms were unevenly distributed (Scheme 2B): the ben-
zylic position was only 64% deuteriated, while the methyl
group was 47% deuteriated. Combined with the observed
isomerization of 1q described above (Table 2), this sug-
gests that H or D atoms may readily migrate between the
benzylic and homobenzylic carbon atoms of 1a.18
Various styrenes were also readily hydrogenated (1x–
1aa), including those bearing electron-donating (1y) and
electron-withdrawing (1z and 1aa) groups; no dehalogen-
ation of 1z was observed. In contrast, styrenes bearing
functional groups sensitive to reducing conditions, such
as a nitro group (1ab), an azide (1ac), and aryl (1ad–1af)
and alkenyl (1ag) bromides afforded low yields of the de-
sired products due to competing functional group reduc-
tion, hydrogenolysis, and styrene polymerization.13 None-
theless, these examples are instructive in that they show
that the reaction conditions can be used to reduce func-
tional groups other than unsaturated C–C bonds.
In our third and final study involving deuterium atoms,
we emp loyed and equimolar mixture of H2O and D2O to
probe the existence of a kinetic isotope effect (Scheme
2C). Subjection of 3c to
This reaction is readily executed on 5.0 mmol scale (Ta-
ble 2, 1a, 1j, and 1q) to afford the corresponding products
in excellent yield. These scaled-up reactions were carried
out using just 0.5 mol % of catalyst; consequently, these
reactions required extended reaction time (60 hours).
Scheme 2. Isotopic Mechanistic Experiments (Note:
Complete Substrate Conversion Occurred in All Cas-
es)
A. Deuterium incorporation
% D
in 4c
The reaction conditions can also be used to reduce al-
kynes (Table 3). In these cases, 2.1 equivalents of tetrahy-
droxydiboron are required to fully reduce the alkyne.
Simple unactivated alkynes including phenyl acetylene
(3a), 1-phenyl-1-propyne (3b), and diphenylacetylene (3c)
were nearly quantitatively hydrogenated to the corre-
sponding alkane products.16
additive (2.1 equiv)
D2O (5 equiv)
additive
B2(OH)4
B2(OH)4
B2(OD)4
B2(cat)2
48
D/H
D/H
Ph
H/D
H/D
94a
98
Pd/C (5 mol %)
Ph
Ph
CH2Cl2 (0.3 M)
rt, 5 h
Ph
3c
4c
98
a Used 50 equiv of D2O
B. Deuterium distribution
B2(OD)4 (1.1 equiv)
D2O (5 equiv)
Pd/C (5 mol %)
uneven
D atom
distribution
¬ 64% D
Ph H/D
Ph
Ph
H
H
Table 3. Scope of The Hydrogenation of Alkynes
CH3/D3¬
47% D
CH2Cl2 (0.3 M)
rt, 5 h
Ph
B2(OH)4 (2.1 equiv)
Pd/C (5 mol %)
2a
1a
R''
+
H2O
(9 equiv)
R'
R''
C. Kinetic isotope effect
B2(cat)2 (2.1 equiv)
CH2Cl2 (0.3 M)
rt, 5 h
R'
3
4
H2O (2.5 equiv)
D2O (2.5 equiv)
Pd/C (5 mol %)
Ph
3a, 95%
H
Ph
Me
3b, 95%
Ph
Ph
D/H
Ph
85:15 H/D ratio
(kH/kD = 5.6)
D/H
Ph
Ph
3c, 98%
H/D
H/D
CH2Cl2 (0.3 M)
rt, 5 h
Ph
3c
4c
Isolated yields are reported, and starting material was con-
sumed in full. Reactions were conducted on 0.6 mmol scale.
our reaction conditions in the presence of an equimolar
mixture of H2O and D2O revealed a primary kinetic iso-
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Supporting Information. Experimental procedures
and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
tope effect of 5.6, suggesting that H atom bond cleavage
1
2
3
4
5
6
7
8
occurs in the rate-determining step of the reaction. For
comparison, the reported catalytic transfer hydrogenation
of the dimethyl ester analog of 1e in the presence of an
equimolar mixture of H2O and D2O using titanocene(III)
afforded no deuteriated product at all.2 Further, a small (<
1.5) deuterium isotope effect is observed for both homo-
and heterogeneous palladium-catalyzed hydrogenation
reactions when using an equimolar mixture of H2 and D2
gas.19
AUTHOR INFORMATION
Corresponding Author
*bstokes2@ucmerced.edu
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The authors declare no competing financial interest.
Based on our observations, we propose the following
putative catalytic cycle for the hydrogenation of alkenes
and alkynes using trans-stilbene 1q as a representative
alkene (Scheme 3). Initial oxidative addition of the B–B
bond to palladium could occur to afford 5. Water could
then coordinate to a Lewis acidic boron atom to afford 6.
H atom transfer could then furnish palladium hydride 7.8
At this point, the alkene could reversibly20 insert into 7 to
give Pd–alkyl 8,21 followed by water coordination and a
second H atom
ACKNOWLEDGMENT
This research was supported by the University of Cali-
fornia, Merced. We thank the reviewers for their in-
sightful suggestions.
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(7) Oxidative additions of diboron reagents to homogeneous Pd
catalysts are known, but rare. See: (a) Burks, H. E.; Liu, S.;
Morken, J. P. J. Am. Chem. Soc. 2007, 129, 8766. For theoretical
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Raducan, M.; Alam, R.; Szabó, K. J. Angew. Chem. Int. Ed. 2012,
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Scheme 3. Putative Catalytic Cycle for Hydrogenation
of trans-Stilbene by Water Using Tetrahydroxydibo-
ron
transfer to give alkyl-Pd-hydride 10. Intermediate 10
could then undergo reductive elimination to give the hy-
drogenated product (2q, in this example).
In conclusion, we have discovered a new method that
hydrogenates alkenes and alkynes quantitatively at ambi-
ent temperature and pressure by stoichiometric atom
transfer from H2O using a diboron additive. We are cur-
rently working to better understand the mechanistic in-
tricacies of this process, including the nature of the active
catalyst and the identity of the rate determining step, in
order to enable the design of new reactions. We are also
investigating new ways to harness this mode of O–H bond
weakening for other transformations.
ASSOCIATED CONTENT
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1
2
3
4
5
6
7
8
Pd/C and water. See the Supporting Information for details.
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Giannici, F.; Longo, A.; Groppo, E. ACS Catal. 2014, 4, 187; (b)
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Cat. Commun. 2006, 7, 896.
(12) (a) Hintermair, U.; Campos, J.; Brewster, T. P.; Pratt, L. M.;
Schley, N. D.; Crabtree, R. H. ACS Cat. 2014, 4, 99; (b) Gieshoff,
T. N.; Villa, M.; Welther, A.; Plois, M.; Chakraborty, U.; Wolf, R.;
Jacobi von Wangelin, A. Green Chem. 2015, 17, 1408; (c) Wide-
gren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem 2003, 198, 317.
(13) See the Supporting Information for complete details.
(14) Molander, G. A.; Trice, S. L. J.; Tschaen, B. Tetrahedron 2015,
71, 5758.
(15) (a) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226; (b)
Muzart, J. Eur. J. Org. Chem. 2015, 2015, 5693.
(16) The use of Lindlar catalyst for the partial reduction of 3c
resulted in no reaction under the conditions optimized for Pd/C.
However, at 35 °C using triethylamine, a 63% NMR yield of cis-
stilbene 1r is observed (eq 1). No attempt was made to optimize
this reaction. See the Supporting Information for details.
(18) Deuterium migration was also observed when using Rh/C
and Pt/C catalysts. See the Supporting Information for details.
(19) Samuel, B.; Ohrt, W. Chem. Commun. 1971, 1529.
(20) A crossover experiment also supports the existence of a
reversible step involving C–H bond cleavage. See the Supporting
Information for details.
(21) The subjection of norbornene 1h to our deuteriation condi-
tions results exclusively in exo deuteriation, implying a syn mi-
gratory insertion. See the Supporting Information for experi-
mental details.
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B2(OH)4 (1.1 equiv)
Pd/C (5 mol %)
R1
R2
R3
R4
R1
R2
R3
R4
+
H2O
DCM, rt
· No H2 gas required
·Stoichiometric H atom transfer from H2O
·Stoichiometric D atom transfer from D2O using B2(OD)4
· Putative hydride generation via:
H
OH
(HO)2B–Pd B(OH)2
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