Catalytic Reductions Without External Hydrogen Gas: Broad Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary Amine

Article abstract of DOI:10.1002/adsc.201901099

Facile reduction of aryl halides with a combination of 5% Pd/C, B₂(OH)₄, and 4-methylmorpholine is reported. Aryl bromides, iodides, and chlorides were efficiently reduced. Aryl dihalides containing two different halogen atoms underwent selective reduction: I over Br and Cl, and Br over Cl. Beyond these, aryl triflates were efficiently reduced. This combination was broadly general, effectuating reductions of benzylic halides and ethers, alkenes, alkynes, aldehydes, and azides, as well as for N-Cbz deprotection. A cyano group was unaffected, but a nitro group and a ketone underwent reduction to a low extent. When B₂(OD)₄ was used for aryl halide reduction, a significant amount of deuteriation occurred. However, H atom incorporation competed and increased in slower reactions. 4-Methylmorpholine was identified as a possible source of H atoms in this, but a combination of only 4-methylmorpholine and Pd/C did not result in reduction. Hydrogen gas has been observed to form with this reagent combination. Experiments aimed at understanding the chemistry led to the proposal of a plausible mechanism and to the identification of N,N-bis(methyl-d₃)pyridin-4-amine (DMAP-d₆) and B₂(OD)₄ as an effective combination for full aromatic deuteriation. (Figure presented.).

Full text of DOI:10.1002/adsc.201901099

Title: Catalytic Reductions Without External Hydrogen Gas: Broad
Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary
Amine
Authors: Kirill Korvinson, Hari Akula, Casina Malinchak, Dellamol
Sebastian, Wei Wei, Tashrique Khandaker, Magdalena
Andrzejewska, Barbara Zajc, and Mahesh Lakshman
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901099
Link to VoR: http://dx.doi.org/10.1002/adsc.201901099

10.1002/adsc.201901099
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Reductions Without External Hydrogen Gas: Broad
Scope Hydrogenations with Tetrahydroxydiboron and a
Tertiary Amine
Kirill A. Korvinson,a, b,† Hari K. Akula,a,† Casina T. Malinchak,a,b,‡ Dellamol Sebastian,a,b,‡ Wei
Wei,a,b,‡ Tashrique A. Khandaker,a Magdalena R. Andrzejewska,a Barbara Zajca,b,* and Mahesh K.
Lakshmana,b,*
a
Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue,
New York, NY 10031 (USA)
E-mail: bzajc@ccny.cuny.edu, mlakshman@ccny.cuny.edu]
The Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New
b
York, NY 10016 (USA)
†Equally contributing first authors. ‡Equally contributing second authors.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Facile reduction of aryl halides with
a
atom incorporation competed and increased in slower
combination of 5% Pd/C, B2(OH)4, and 4-methylmorpholine reactions. 4-Methylmorpholine was identified as a possible
is reported. Aryl bromides, iodides, and chlorides were source of H atoms in this, but a combination of only 4-
efficiently reduced. Aryl dihalides containing two different methylmorpholine and Pd/C did not result in reduction.
halogen atoms underwent selective reduction: I over Br and Hydrogen gas has been observed to form with this reagent
Cl, and Br over Cl. Beyond these, aryl triflates were combination. Experiments aimed at understanding the
efficiently reduced. This combination was broadly general, chemistry led to the proposal of a plausible mechanism and
effectuating reductions of benzylic halides and ethers, to the identification of N,N-bis(methyl-d3)pyridine-4-amine
alkenes, alkynes, aldehydes, and azides, as well as for N-Cbz (DMAP-d6) and B2(OD)4 as an effective combination for
deprotection. A cyano group was unaffected, but a nitro full aromatic deuteriation.
group and a ketone underwent reduction to a low extent.
When B2(OD)4 was used for aryl halide reduction, a
significant amount of deuteriation occurred. However, H
Keywords: reduction; diboron; tetrahydroxydiboron;
hydrogenation; deuteriation
powerful reductant of pyridine N-oxides,[8] for
converting 1-hydroxy-1H-benzotriazoles to 1H-
benzotriazoles under mild conditions,[9] and recently,
in the regiospecific N-arylation of benzotriazoles.[10]
Whereas these reactions rely on B–B to B–O–B bond
conversion, a different type of reduction was reported
in 2016, involving B2(OH)4, Pd/C, and H2O.[11] Here,
hydrogen atoms for the reduction of CC and CC
arose from water. Subsequently, B2(OH)4 and H2O
were used in metal-free reductions of quinolines and
quinazolines,[12] and in the reduction step of
cyclization-reductive Heck reactions.[13]
Introduction
Diboron compounds, known for over 90 years,[1] have
emerged from being chemical curiosities to powerful
reagents in organic synthesis.[2,3] Among reactions
that do not involve substrate borylation, reductions by
diboron reagents are rising in importance. The
possibility for reducing amine N-oxides by
bis(pinacolato)diboron
(pinB)2
and
bis(catecholato)diboron (catB)2 was demonstrated in
2002 with two pyridine N-oxides and 4-
methylmorpholine-N-oxide.[4] Since then, (pinB)2 has
been used to reduce N–O bonds in O6-(benzotriazol-
1-yl)purine nucleosides, leading to C-6 benzotriazol-
The combination of (pinB)2 and H2O has been the
focus of several reduction protocols. In the presence
of Pd(OAc)2, quinolines, quinoxalines, and
1-yl
nucleoside
analogues,[5]
and
N-
hydroxyphthalimides.[6] (PinB)2 and (catB)2 are
broadly applicable for the reduction of amine N-
oxides and the former is suitable for reduction under
aqueous conditions as well.[7] Subsequently,
tetrahydroxydiboron (B2(OH)4) has featured as a
1
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Table 1. Evaluation of conditions for the reduction of 9-bromophenanthrene to phenanthrene.
Entry “Pd” (mol %) B2(OH)4 (equiv.) Additive (equiv.)
Conditions
Result[a]
Inc[c]
1[b]
2[b]
3[b]
4[b]
5[d]
6[d]
7[d]
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
Pd2(dba)3 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
1.1
1.1
2.2
1.1 × 2
3.0
H2O (5)
H2O (5)
H2O (5)
CH2Cl2, rt, 20 h
1,2-DCE, 50 °C, 18 h, then 80 °C, 72 h
1,2-DCE, 80 °C, 18 h
Inc[c]
Inc[c]
98%
pyrrolidine (5 × 2) 1,2-DCE, 50 °C, 24 h, then 50 °C, 20 h
[e]
H2O (10)
H2O (10)
H2O (10)
1,2-DCE, 50 °C, 19 h, then 100 °C, 72 h
1,2-DCE, 50 °C, 22 h
1,2-DCE, Cs2CO3 (2.5 equiv.), 50 °C, 19
h, then 100 °C, 72 h
1,2-DCE, 50 °C, 1.5 h
1,2-DCE, 50 °C, 1.5 h
1,2-DCE, 50 °C, 1.5 h
1,2-DCE, 50 °C, 24 h
1,2-DCE, 50 °C, 22 h
1,2-DCE, 50 °C, 24 h
–
–
–
[e]
3.0
3.0
[e]
8[d]
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
none
2.2
2.2
2.2
2.2
0
pyrrolidine (5)
pyrrolidine (10)
pyrrolidine (5)
H2O (10)
pyrrolidine (5)
none
98%
9[f]
94%[g]
100%
Inc[c]
NR[h]
NR[h]
10[f]
11[f]
12[f]
13[f]
2.2
2.2
14[f]
pyrrolidine (5)
1,2-DCE, 50 °C, 24 h
–
[e]
[a]
Yield reported is of purified phenanthrene from reactions where little or no 9-bromophenanthrene remained.
Reaction was conducted with 0.6 mmol of 9-bromophenanthrene at a concentration of 0.3 M in the solvent.
Inc = incomplete reaction, a significant amount of 9-bromophenanthrene remained.
Reaction was conducted with 0.2 mmol of 9-bromophenanthrene at a concentration of 0.1 M in 1,2-DCE.
A trace amount of phenanthrene was observed.
Reaction was conducted with 0.2 mmol of 9-bromophenanthrene at a concentration of 0.3 M in 1,2-DCE.
A trace amount of 9-bromophenanthrene remained.
NR = no reaction was observed.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
imidazo[2,1a]pyridines were reduced (with or
without added base),[14] and imidazo[2,1a]pyridines
with added PCy3.[15] Aldehydes and ketones were
reduced in the presence of DBU, without
Results and Discussion
Pd(OAc)2,[16] but with Pd(OAc)2 and Cs2CO3
a
Our initial hypothesis (Scheme 1) was that use of a
secondary amine could likely result in a strong N–B
bond with the boron, after the oxidative addition.
Thus, a significantly weakened N–H bond could
facilitate formation of a “Pd-H” species, which could
reduce an aryl halide. Presence of excess amine could
then regenerate Pd(0). On the basis of this rationale,
quinoline and a pyridine underwent ring reduction,
and benzonitrile was reduced to benzylamine.[16] With
CuBr/Cs2CO3, enones and ynones underwent -
borylation
with
(pinB)2
to give
Similarly,
pathway
followed
by
protiodeboronation
the
reduction
products.[17,18]
borylation/protiodeboronation
a
with
CuBr/Xantphos/Cs2CO3 has been utilized for the
reduction of benzofuranyl ketones.[19]
In these reactions, whenever an aromatic halogen
atom was present, it remained unaffected. Notably,
under the olefin-reducing conditions,[11] an aryl
chloride was not reduced, although partial reduction
of a bromide, azide, and a nitro group were observed
(with partial conversion of substrates).[11] A number
of well-established as well as recent methods are
available for the reduction of aryl halides.[20–22]
However, we were interested in assessing whether
aryl halide reduction could be accomplished with a
diboron reagent and, if successful, we wished to
evaluate the reduction of other functionalities. Such a
method would dispense with a need for external,
stored hydrogen gas.
Scheme 1. An initially proposed mechanism for the
reduction of aryl halides to arenes.
2
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Table 2. Influence of other nitrogen-containing additives on the reduction of 9-bromophenanthrene to phenanthrene.[a]
Entry “Pd” (mol %)
Solvent, additive
Temperature, time
Result[b]
[c]
1
2
3
4
5
6
7
8
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
5% Pd/C (5)
Pd(OAc)2 (5)
1,2-DCE, NH3
1,2-DCE, Et3N
1,2-DCE, iPr2NEt
1,2-DCE, PhNHMe
1,2-DCE, 4-methylmorpholine
1,2-DCE, 1-methylpyrrolidine
THF, 4-methylmorpholine
MeCN, 4-methylmorpholine
THF, none
50 °C, 1 h
50 °C, 1.5 h
50 °C, 24 h
50 °C, 24 h
50 °C, 1 h
50 °C, 1 h
50 °C, 6.5 h
50 °C, 6.5 h
50 °C, 5 h
50 °C, 5 h
50 °C, 3.5 h
50 °C, 30 h
50 °C, 21 h
50 °C, 21 h
100%
92%
64%[d]
[e]
–
99%
98%
74%[d]
97%
[e]
9
–
–
[e]
10
11
12
13
14
15
MeCN, none
C6H5CH3, 4-methylmorpholine
C6H6, 4-methylmorpholine
1,2-DCE, 4-methylmorpholine
99%
97%
Inc[d]
Inc[d]
Pd2(dba)3 (2.5) 1,2-DCE, 4-methylmorpholine
none 1,2-DCE, 4-methylmorpholine
50 °C, 2 h, 5 h, and NR[g]
then 21 h
[a]
Reactions were conducted with 0.2 mmol of 9-bromophenanthrene at a concentration of 0.3 M in the solvent, with
2.2 equiv. of B2(OH)4, and 5 equiv. of the additive.
Yield reported is of purified phenanthrene from reactions where little or no 9-bromophenanthrene remained.
7 M NH3 in MeOH was used.
Inc = incomplete reaction.
A trace amount of phenanthrene was observed.
[b]
[c]
[d]
[e]
[f]
A trace amount of 9-bromophenanthrene remained.
NR = no reaction was observed.
[g]
evaluations commenced on 9-bromophenanthrene (a
selection is shown in Table 1). The B2(OH)4 used for
3). By contrast, N-methylaniline was ineffective
(entry 4). In this connection, partial reduction of
diphenylacetylene with Lindlar catalyst and Et3N has
been shown (71% substrate consumption).[11]
1
these reactions was analyzed on the basis of the H
integration values and known chemical shifts.[23] It
became immediately evident that the combination of
Pd/C, B2(OH)4, and H2O, which efficiently reduced
olefins and alkynes,[11] was ineffective here (entries
1–3). However, as hypothesized, Pd/C and
pyrrolidine led to reduction, but 2 aliquots ofB2(OH)4
and pyrrolidine were needed to attain a complete
reaction (entry 4). Pd2(dba)3/H2O and Pd(OAc)2/H2O
were ineffective (entries 5–7). Further optimizations
(entries 8–10) showed 2.2 equiv. of B2(OH)4 and 5
equiv. of pyrrolidine to be optimal. Doubling the
amount of pyrrolidine appeared to lead to a slightly
incomplete reaction (entry 9), and even on a lower
scale water was less effective (entry 11). Absence of
B2(OH)4, or pyrrolidine, or Pd/C led to practically no
reaction (entries 12–14).
Other amines were then evaluated for the reduction
of 9-bromophenanthrene (Table 2). NH3 in MeOH
gave a rapid reaction and bubbling was observed
(likely evolution of H2 gas, entry 1). Here, NH3
and/or MeOH could be a source of hydrogen as was
the case with H2O. More interestingly though,
reduction also occurred with tertiary amines Et3N and
iPr2NEt, but the latter was less efficient (entries 2 and
Remarkably,
4-methylmorpholine
and
1-
methylpyrrolidine gave rapid reactions, and proved to
be slightly better than Et3N (entries 5 and 6).
Between the two, the cheaper 4-methylmorpholine
was selected for further evaluations. Between THF
and MeCN, the latter was a better solvent, but 1,2-
DCE was superior (entry 5 versus entries 7 and 8).
In THF and MeCN only a trace of product was
observed in the absence of an amine (entries 9 and
10). By comparison, 1,1-diphenylethylene was
reported to undergo reduction with B2(OH)4 with
variable efficiency in THF in the absence of H2O.[11]
A reaction in toluene was satisfactory (entry 11) but
slightly slower than that in 1,2-DCE, and a reaction in
benzene was very slow (entry 12). Whereas Pd(OAc)2
and Pd2(dba)3 were ineffective in combination with
water, much better but incomplete conversions were
observed with 4-methylmorpholine (entries 13 and
14). Under otherwise comparable conditions, (pinB)2
in place of B2(OH)4 led to only a trace amount of
phenanthrene over 55 h. However, with (catB)2, a
72% yield of phenanthrene was obtained after 24 h
3
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Figure 1. Products from the reduction of aryl halides and triflates, reaction times, and yields. The locations of the halogen
[a]
atom or triflate in the precursors are the positions occupied by the hydrogen atoms shown in blue in the products.
Product is potentially volatile. [b] Yield was assessed using CH2Br2 as an internal 1H NMR standard.
(ca. 80% conversion). To test whether H3BO3, present
in B2(OH)4, was responsible for the reduction, 2.2
equiv. of H3BO3 was evaluated but it led to no
reaction over 24 h. Thus, it is safe to surmise that
B2(OH)4, its dimer, and possibly the trace amount of
trimer are involved in this reduction. The amount of
4-methylmorpholine necessary for the reduction was
assessed and with 1 and 2 equiv., reductions were
only ca. 50% complete. At 3 equiv. the reduction
reached completion within 7 h, at 4 equiv. the
reaction time was a shorter 80 min, and at 5 equiv.
the reaction was complete within 1 h (product yield
was 99% in these three cases and incomplete
reactions were observed with <3 equiv. of 4-
methylmorpholine).
the outcomes with chloro substrates were of
particular interest. In addition to aryl bromides and
chlorides, some aryl iodides and mixed aryl dihalides
were also studied. The results from the reductions of
these substrates using 2.2 equiv. of B2(OH)4 and 5
equiv. of 4-methylmorpholine, in 1,2-DCE at 50 °C
are shown in Figure 1. Insofar as possible, isolated
product yields are reported, although product
volatility may have contributed to lowered yields in
some cases. In instances where product isolation was
precluded due to volatility, yields were estimated by
1H NMR analysis of the crude reaction mixtures
using CH2Br2 ( = 4.93 ppm in CDCl3) as an internal
standard.
Products 1–12 were all obtained in good to
excellent isolated yields. Notably, the bromophenyl
crown ether and 3-bromoindazole were reduced
smoothly, giving 8 and 10, respectively. N,N-
Twenty-nine halogenated substrates were selected
for further analysis and because an aryl chloride was
not reduced under previously reported conditions,[11]
4
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Dimethylaniline (12) was obtained quantitatively (as
required a modified stoichiometry (4.4 equiv.) of
B2(OH)4 and this is indicated in Figure 2. 1-
Chloromethyl and 2-bromomethylnaphthalene were
reduced to the corresponding methylnaphthalenes, 27
1
assessed by H NMR). Reduction of all three p-halo
benzoic acids proceeded well to yield benzoic acid
(13), except that a longer reaction time was needed
for reduction of the iodo precursor. Similarly, p-halo
acetanilides also underwent smooth reduction to
acetanilide (14), with the iodo analogue reacting
slower. These conditions did not cause reduction of
p-fluoroacetanilide and this substrate could not be
reduced with Pd/C and NH3 in MeOH or with
(cod)2Ni and 4-methylmorpholine. 3-Bromoquinoline
underwent reduction to quinoline (15) in a high yield
and no ring reduction was observed. In contrast to
this, 2-chloroquinoline underwent reduction to yield
quinoline (15) and 1,2,3,4-tetrahydroquinoline
(1,2,3,4-H4Q, 14% yield). p-Toluidine (16), p-
methoxyacetophenone (17), 1,3-benzodioxole (18),
and 2-methoxypyridine (19) were obtained by
reduction of the respective aryl chlorides. Notably, a
keto group was not affected and neither was the
and
28,
respectively.
Interestingly,
2-
(phenoxymethyl)naphthalene[34] was also reduced to
2-methylnaphthalene (28) in a high yield, comparable
to 2-bromomethylnaphthalene. Because this result
represented benzylic hydrogenolysis of an ether,
yielding the hydrocarbon, debenzylation of 2-
benzyloxypyridine and 4-benzyloxyquinazoline[35]
were evaluated. These reactions returned excellent
yields of 2-pyridone (2-hydroxypyridine, 29) and 4-
quinazolinone (30), respectively. On the basis of
these debenzylation reactions, cleavage of the Cbz-
protection from amines was attempted. 1-
Naphthylamine (31) was obtained smoothly from
benzyl
naphthalen-1-ylcarbamate.[36]
Next,
debenzylation of the N-Cbz derivative of (R)-1-(1-
naphthyl)ethylamine[37] was evaluated. This reaction
was complete within 24 h. However, in the H NMR
1
pyridine ring.
A
chloro nucleoside derivative
underwent efficient, uncomplicated reduction to the
protected nebularine 20.[24] The reactions of mixed
halo arenes proved interesting. Two chloro-iodo
arenes underwent selective C–I bond reduction,
resulting in products 21 and 22. The reaction of a
bromo-iodo arene also proceeded well, selectively
spectrum of the crude material, the CH (quartet) and
the CH3 (doublet) were slightly downfield shifted as
compared to the authentic product (Figure 1 in the
Supporting Information). This could be due to the
formation of an amine-boron complex from a
relatively basic alkyl amine. Stirring the crude
product with ethylenediamine, followed by
purification resulted in chemical shifts that exactly
matched that of the authentic material (evaluated at
identical concentrations, Figure 1 in the Supporting
Information). In contrast to these results,
debenzylation was not observed under the previously-
described olefin-reducing conditions involving
H2O.[11]
Reduction of trans-cinnamyl alcohol to 3-phenyl-
1-propanol (33), trans-stilbene to 1,2-diphenylethane
(34), and 4-aminostyrene to 4-ethylaniline (35)
proceeded smoothly. The trisubstituted olefin in ()-
citronellol was reduced to yield (±)-3,7-
dimethyloctan-1-ol (36) in a good yield. Reduction of
cinnamyl acetate[38] was studied to assess whether
only olefin reduction or complete reduction occurred.
With 2.2 equiv. of B2(OH)4, a small amount of 1-
phenyl-1-propene was visible in the 1H NMR
spectrum of the reaction mixture. However, use of 4.4
equiv. of B2(OH)4 led to full reduction, yielding
propyl benzene (37). Next, the reduction of 3-phenyl-
2-propyn-1-ol was assessed, where use of 4.4 equiv.
of B2(OH)4 and 10 equiv. of 4-methylmorpholine
gave 3-phenyl-1-propanol (33) reasonably efficiently
(use of 5 equiv. of 4-methylmorpholine gave a
comparable outcome). Along similar lines, 1-ethyl-
2,4,5-trimethylbenzene (38) was obtained from 1-
ethynyl-2,4,5-trimethylbenzene with 4.4 equiv. of
B2(OH)4 and 5 equiv. of 4-methylmorpholine (again,
use of 10 equiv. of 4-methylmorpholine gave a
producing 23. Reduction of
a
3-bromo-4-
chlorobenzoic acid returned p-chlorobenzoic acid
(24) in good yield, with about 7% of benzoic acid
being formed. In some reactions, a small amount (≈
5–7%) of biaryl formation was observed (please see
the Supporting Information for details).
Interestingly, phenol triflates were also reduced
(Figure 1). Previously, phenol triflates have been
reduced with a combination of a Pd catalyst,
phosphine ligand, and an amine (with or without an
acid additive), with formate often serving as a source
of hydrogen atoms.[25–28] Under the conditions
described here, the triflate derivative of 4-
acetaminophen[29] was reduced in high yield to
acetanilide (14). By comparison to the easy
reducibility of this triflate, the tosylate and mesylate
derivatives underwent reduction in only 5% and 22%
1
yields, respectively (as assessed by H NMR). 6-
Hydroxyquinoline triflate[30] underwent reduction to
quinoline (15) in good yield, accompanied by some
ring reduction (1,2,3,4-H4Q, 16% yield), an outcome
comparable to that from 2-chloroquinoline (Figure 1).
o-Hydroxypropiophenone
triflate[31]
underwent
reduction to propiophenone (25), accompanied by
over reduction to 1-phenyl-1-propanol (1-Ph-1-PrOH,
31% yield). The extent of the carbonyl reduction in
this case could be due to the proximity of the two
reducible functionalities. The steroidal estrone
triflate[32] also underwent reduction in high yield to
the deoxygenated analog 26.[33] These combined
results show the facile reducibility of the C–OTf
bond.
similar
yield).
1-Naphthaldehyde,
1-
pyrenecarboxaldehyde,
trimethoxybenzaldehyde,
3,4,5-
In order to ascertain the broader utility of these
reduction conditions, other functionalities were tested
(Figure 2). In this experimentation, some substrates
4-cyanobenzaldehyde,
quinoline-6-carbaldehyde, and 2-
5
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Figure 2. Reduction of benzylic halides, benzylic ethers, a Cbz derivative, alkenes, an allyl acetate, alkynes, aldehydes,
[a]
[b]
and azides. Product is potentially volatile.
Reaction was conducted with 2.2 equiv. of B2(OH)4 and 5 equiv. of 4-
[c]
[d]
methylmorpholine.
Reaction was conducted with 4.4 equiv. of B2(OH)4 and 5 equiv. of 4-methylmorpholine.
[e]
Reaction was conducted with 4.4 equiv. of B2(OH)4 and 10 equiv. of 4-methylmorpholine.
sublimation under reduced pressure.
Product was prone to
1
benzofurancarboxaldehyde all underwent reduction to
the corresponding alcohols (39–44). In the case of
3,4,5-trimethoxybenzaldehyde, 4.4 equiv. of B2(OH)4
was used in order to attain complete conversion. The
slow reduction in this case may be due to the
mesomeric effect of the p-methoxy group. As a note,
and reduction of the aryl azides. The H NMR data
of 46 was consistent with the literature data.[40]
The reducibility of other functional groups was
assessed.
In contrast to the reduction of 1-
pyrenecarboxyaldehyde, 1-cyanopyrene was not
reduced (24 h, 50 °C), but 6-nitroindole gave a 22%
yield of the amine (24 h, 50 °C, 50% of starting
material was recovered). Aryl nitro groups have
previously been reduced with (pinB)2/t-BuOK/iPrOH
at 110 °C, (pinB)2/KF/EtOH at 100 °C, Pd on
in
the
reduction
of
3’-chloro-4’-
methoxyacetophenone (Figure 1), the keto group was
not reduced, in contrast to the 12% reduction of 1-
acetonaphthone (vide infra). Finally, three azides
were tested. Among these, 4-tolylazide required 4.4
equiv. of B2(OH)4 for complete reduction to 4-
toluidine (16). On the other hand, 5-azido-2-
methoxypyrimidine[39] and 5’-O-TBDMS-protected
3’-azido-3’-deoxythymidine were smoothly reduced
to the corresponding amino derivatives 45 and 46[40]
with 2.2 equiv. of B2(OH)4. In contrast to the
deprotection of benzyl (R)-(1-(naphthalen-1-
yl)ethyl)carbamate where amine-boron complexation
likely occurred, this did not seem to occur in the
C/B2(OH)4
and
water
at
50
°C,
or
Cu(OAc)2/B2(OH)4/MeCN at 80 °C, without
reduction of a C-halogen bond where tested.[41–44] 1-
Acetonaphthone gave a 12% yield of the alcohol (24
h, 50 °C, 87% of starting material was recovered). In
order to learn whether 1,2-DCE underwent reduction
under the conditions, 3-phenyl-1-chloropropane was
subjected to the reaction conditions. 1-Phenylpropane
was formed to an extent of 15% in 24 h (by 1H NMR).
The previously reported reduction of 6-chloro-1-
reduction
of
TBDMS-protected
3’-azido-3’-
hydroxy-1H-benzotriazole
(47)
presented
an
deoxythymidine, Cbz cleavage from the aryl amine,
interesting case study for two experiments (Scheme
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901099
Advanced Synthesis & Catalysis
2).[9] In one experiment, the N–OH group was first
reduced with B2(OH)4 and Et3N in MeCN at 50 °C to
yield intermediate 48,[9] followed by reduction of the
C–Cl bond with B2(OH)4 and 4-methylmorpholine in
the same reaction vessel, to give benzotriazole (49).
The second experiment was a one-step reduction of
47 to 49 using Pd/C, B2(OH4), and 4-
methylmorpholine. Both reactions proceeded well
and, notably, reduction of the N–O and C–Cl bonds
could be accomplished within 2 h by the one-step
method.
Table 3. Reduction of 9-bromophenanthrene with B2(OD)4,
4-methylmorpholine, and 5% Pd on carbon.[a]
Entry Solvent
Time
Deuteriation [%]
1
2
3
4
5
6
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE-d4 1.5 h
C6H6
C6D6
1.5 h
68
76
73
70
48
46
1.5 h[b]
1.5 h[c]
30 h
30 h
[a]
Reactions were conducted with 0.2 mmol of 9-
bromophenanthrene at a concentration of 0.3 M in the
solvent.
Pd/C was washed thrice with CH3OH, once with 1,2-
DCE, and vacuum dried.
[b]
[c]
Pd/C was washed thrice with CD3OD, once with 1,2-
DCE, and vacuum dried.
Scheme 2. Two-step, one-pot, and a one-step
reduction of 6-chloro-1-hydroxy-1H-benzotriazole.
NMR experiments did not readily provide insight
The source of hydrogen atoms for the reduction
was then probed. For this B2(OD)4 was prepared as
to mechanistic details. However, from the data in
Table 3, key information is discernible. Deuterium
atoms from B2(OD)4 and by inference, hydrogen
atoms from B2(OH)4, become available for the
reduction, but competitive hydrogen atom
incorporation is observed during deuteriation. In
comparing entries 1 and 4, no deuterium atoms (and
by inference, hydrogen atoms) seem to be obtained
from the solvent. By exclusion, this leaves 4-
methylmorpholine as a source of hydrogen atoms.
The unavailability/high cost of deuterated alkyl
amines precluded evaluations with one. When
reactions were relatively fast (entries 1–4) the
proportion of deuteriation was greater as compared to
the much slower reactions in C6H6 or C6D6, where
nearly equal amounts of H and D were incorporated
(entries 1–4 versus entries 5 and 6). Thus, D/H
exchange appears possible along the reaction path,
which could then account for the greater
incorporation of H in the slower reactions. A reaction
using B2(OH)4 and 4-methylmorpholine in 1,2-DCE,
with 2 equiv. of D2O, resulted in only a 12%
incorporation of D. This shows that H atom
incorporation from adventitious moisture is not a
likely cause for the observed results and that H/D
exchange with the diboron is a slow process. These
results collectively point to the possibility that a
significant proportion, but not all of the hydrogen
atoms for the reduction may be obtained from the
1
previously described.[11] Its H NMR spectrum (in
DMSO-d6) indicated the absence of protons (attempts
to conduct H/D exchange on B2(OH)4 by multiple
treatments with CD3OD and evaporations indicated a
slow and incomplete exchange). Six reactions were
conducted with B2(OD)4 (Table 3). Under the
optimized conditions, 68% incorporation of D was
observed and this improved to 76% upon washing the
Pd/C with CH3OH, 1,2-DCE, and drying under
vacuum (entries 1 and 2). This was not significantly
altered when the washing was performed with
CD3OD (entry 3). A reaction in 1,2-DCE-d4 (entry 4)
indicated that the hydrogen atoms did not arise from
the solvent. Reactions in benzene and benzene-d6
were essentially comparable but the extents of
hydrogen atom incorporation were much greater than
in 1,2-DCE (entries 5 and 6).
diboron reagent. From
a
reaction of 9-
bromophenanthrene under the optimized conditions,
1
the headspace of the mixture was analyzed by H
NMR. This showed a resonance at  = 4.62 ppm (in
CDCl3), the reported value for H2 in CDCl3,[45] and
GC analysis also indicated the formation of H2
(Figures 2 and 3 in the Supporting Information).
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901099
Advanced Synthesis & Catalysis
Deuteriation then became a focus and because
exchange process in the deuteriation. Lewis acid-base
interaction of the boron and amine is inadequate,
because a mixture of Pd/C, BF3•Et2O, and 4-
methylmorpholine was ineffective. Thus, the
combination of B2(OH)4, 4-methylmorpholine, and
Pd/C appears uniquely capable of reduction.
appropriate deuteriated alkyl amines are not readily
available, assessments were conducted with amines
that can be easily deuteriated. N,N-Dimethylaniline,
1,2,2,6,6-pentamethylpiperidine,
and
4-N,N-
dimethylaminopyridine (DMAP) were evaluated for
the reduction of 9-bromophenanthrene (Table 4 in the
Supporting Information). Nearly complete reduction
occurred with N,N-dimethylaniline, but over 68 h. A
surprising result was obtained with 1,2,2,6,6-
Mechanistically, amines interact with PdII and Pd0,
and are reductants of the former.[46–49] Of relevance
here, Pd0 is known to react with amines containing -
and -hydrogen atoms, to form hydrido-Pd species,
pentamethylpiperidine where, in addition to reduction, via imine and enamine formation.[46,47] In deuteriation
nearly 50% of 9,9’-biphenanthrene was obtained (in
10 h), a result apparently connected to the mechanism
(vide infra). DMAP gave a promising 99% yield of
phenanthene (1) within 3.5 h (no reduction occurred
without B2(OH)4). Being a slower reaction (3.5 h
versus 1.5 h with 4-methylmorpholine), only 52%
deuteriation occurred when B2(OD)4 and DMAP were
employed. With N,N-bis(methyl-d3)pyridine-4-amine
(see the Supporting Information for its preparation)
and B2(OD)4, six substrates were deuteriated (Scheme
3) in high yields and with high deuterium
incorporation. These results support the hypothesis
that hydrogen atoms from the diboron and the amine
become available for the reductions.
experiments, greater incorporation of D was observed
at the -position in tertiary amines.[47] n-Bu3N,
1,2,2,6,6-pentamethylpiperidine,
1,4-dioxane,
Me2NH formed from DMF at temperatures >120 °C,
and Et3N are known reductants in reactions catalyzed
by Pd complexes.[26,28,50–52] Of particular note, Pd/C
and Et3N have been used for reducing ,-
unsaturated carbonyls and a nitrile (at 120–200 °C)
but, under the conditions, a vinyl chloride was not
reduced at 140 °C.[53]
Scheme 3. Six deuteriated products that were synthesized
using DMAP-d6. The locations of the halogen atom in the
precursors are the positions occupied by the deuterium
atoms shown in blue in the products.
Scheme 4. Potential imine-Pd and enamine-Pd complexes
that can be formed (A) and a plausible mechanism for the
reduction of aryl halides and triflates (B).
On the basis of the foregoing, it is reasonable to
anticipate that amine-Pd0 interactions alone,
producing “Pd–H” intermediates, could lead to the
reduction of aryl halides. However, in 1,2-DCE at 50
oC, no reduction occurred with 5% Pd/C and 4-
methylmorpholine without B2(OH)4. Also, reported
reductions involving amines generally require higher
reaction temperatures. Thus, imine-PdH and
enamine-PdH2 species (Scheme 4A) are likely not
direct reductants but could contribute to a D/H
A possible mechanism (Scheme 4B) involves
oxidative-addition complex I reacting with an amine-
boron complex II, resulting in III. From III, one
possibility is the direct formation of Ar–Pd–H (V) by
transfer of “H” from the B–OH bond to the Pd center,
with expulsion of metaborate (O=B–OH). Ar–Pd–H
(V) could then lead to the reduced product. Whereas
metaborate formation has been postulated in a
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901099
Advanced Synthesis & Catalysis
reduction of nitroarenes by B2(OH)4,[44] in the
absence of evidence for its formation, this remains
speculative. As an alternate, a second amine can bind
at the boron center in III to give species IV from
which formation of V can lead to reduction. It is
currently unclear how H/D from the diboron and/or
amine becomes attached to the Pd center but this can
explain the partial deuteriation observed with
B2(OD)4/4-methylmorpholine.
With DMAP-d6/B2(OD)4 complete deuteriation
occurred. The use of 1,2,2,6,6-pentamethylpiperidine
is interesting in this context, where the reaction took
10 h to reach completion, possibly due to the steric
bulk of this amine. This factor could slow the
conversion of III to IV as well, promoting greater
Miyaura borylation,[54] and increasing the secondary
cross coupling leading to the biaryl. Thus, the minor
amounts of biaryl observed with 4-methylmorpholine
could be due to this process, which becomes
amplified when 1,2,2,6,6-pentamethylpiperidine is
used. “PdH2” as a reductant can also be formed as in
Scheme 1. The hydrogen gas produced could account
for the reduction of carbon-carbon unsaturation and
azide functionality, as well as cleavage of benzyl and
Cbz groups. Transfer hydrogenation[55,56] could
account for aldehyde reduction.
In the context of amine-diboron interactions,
synthesis of the sp3–sp3 diboron species 2,2’-
bi(1,3,6,2-dioxazaborocane) was recently reported.[57]
This entity produces H2 with water and has been used
for reducing alkenes and for the partial hydrogenation
of alkynes.[57] This is reminiscent of the reduction of
amine N-oxides by tetraethyldiborane, forming H2 in
the process.[58] Evidence suggests that 2,2’-bi(1,3,6,2-
dioxazaborocane) may form a borohydride and a
borinic acid that recombine, to produce H2.[57]
Because a borohydride could be formed from 2,2’-
bi(1,3,6,2-dioxazaborocane), aldehydes and ketones
were reduced.[57] By comparison to this reaction, the
present work demonstrates a uniquely new reductive
capability of B2(OH)4, in combination with Pd/C and
a tertiary amine.
of hydrogen atoms. The extent of deuteriation
decreased with longer reaction times, indicating
possible D/H exchange along the reaction path. On
the basis of the mechanistic knowledge gained, aryl
deuteriation was achieved using N,N-bis(methyl-
d3)pyridine-4-amine in combination with B2(OD)4.
The unusual reactivities of diboron reagents
constitute an emerging field and this work, by
comparison to others, shows how subtle variations of
conditions can result in markedly different outcomes.
Experimental Section
Please see the Supporting Information for general
experimental considerations.
General
method
for
the
reduction
[9-
bromophenanthrene  phenanthrene (1)]
To a solution of 9-bromophenanthrene (257.1 mg, 1 mmol)
in DCE (3.3 mL) in a 8 mL vial equipped with a micro stir
bar, was added B2(OH)4 (197.2 mg, 2.2 mmol), 5% Pd/C
(106.5 mg, 0.05 mmol), and 4-methylmorpholine (NMM,
0.55 mL, 5 mmol). The vial was tightly capped and the
reaction mixture was stirred at 50 °C for 1.5 h. The
mixture was then filtered through Celite and the residue
was washed with EtOAc (100 mL). The filtrate was
concentrated under reduced pressure. Purification on a
silica column packed in hexanes and eluted with hexanes
gave 177.5 mg (99% yield) of compound 1 as a white solid.
(In some reactions small amounts of the known 9,9’-
biphenanthrene was isolated.[59]
)
Similar conditions, with any noted variations, were used
for the other transformations.
General method for the reduction of benzoic acids
To a solution of the halo benzoic acid (1 mmol) in DCE
(3.3 mL) in a 8 mL vial equipped with a micro stir bar,
were added B2(OH)4 (197.2 mg, 2.2 mmol), 5% Pd/C
(106.5 mg, 0.05 mmol), and 4-methylmorpholine (NMM,
0.55 mL, 5 mmol). The vial was tightly capped and the
reaction mixture was stirred at 50 °C until full conversion
of the starting material. The mixture was then filtered
through Celite and the residue was washed with EtOAc
(100 mL). The filtrate was concentrated under reduced
pressure. To the crude product (a sticky solid) 1 M HCl (10
mL) was added. The white precipitate was filtered and
dried under vacuum to give the corresponding pure product.
Conclusion
In summary, we set out to assess whether reduction
of aryl halides by B2(OH)4 is achievable. We found
that the combination of 5% Pd/C, B2(OH)4, and 4-
methylmorpholine in 1,2-DCE can effectuate
reductions of aryl and benzylic halides, aryl triflates,
benzylic ethers, alkenes, alkynes, azides, and
deprotection of the N-Cbz functionality, under mild
conditions. 4-Methylmorpholine is a cheap, volatile
reagent that does not complicate compound
purifications. Formation of H2 gas from the
combination of B2(OH)4, 4-methylmorpholine and
Acknowledgements
This work was supported by grants CHE-1265687 and CHE-
1565754 from the National Science Foundation to MKL and BZ,
respectively, as well as PSC CUNY awards to MKL and BZ.
Infrastructural support at CCNY was provided by NIH grant
G12MD007603 from the National Institute of Minority Health
and Health Disparities. We thank Dr. W. Li and Professor T.
Bandosz (CCNY) for their assistance with the detection of
hydrogen gas by GC analysis, and Professor B. Stokes
(University of California, Merced) for helpful discussions.
Frontier Scientific and Allylchem are thanked for samples of the
diboron reagents used in this work.
1
5%Pd/C was observed by H NMR and GC analysis.
Experiments with B2(OD)4 indicated significant
availability of deuterium atoms from the diboron
reagent, but deuteriation was not exclusive, and 4-
methylmorpholine was identified as a possible source
9
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10.1002/adsc.201901099
Advanced Synthesis & Catalysis
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10.1002/adsc.201901099
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