4,4′-Bipyridyl-Catalyzed Reduction of Nitroarenes by Bis(neopentylglycolato)diboron

Article abstract of DOI:10.1021/acs.orglett.9b03419

4,4′-Bipyridyl worked as an organocatalyst for the reduction of nitroarenes by bis(neopentylglycolato)diboron (B₂nep₂), followed by hydrolysis to give the corresponding anilines. This reduction proceeded under aerobic conditions without any prepurification of substrates and reagents. We found broad functional group tolerance and compatibility for O- A nd N-protecting groups under the reaction conditions. The key in this catalytic system was the addition of B₂nep₂ to 4,4′-bipyridyl to form N,N′-bis[(neopentylglycolato)boryl]-4,4′-bipyridinylidene as a deoxygenating reagent of nitroarenes.

Full text of DOI:10.1021/acs.orglett.9b03419

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
4,4′-Bipyridyl-Catalyzed Reduction of Nitroarenes by
Bis(neopentylglycolato)diboron
Hiromu Hosoya,† Luis C. Misal Castro,† Ibrahim Sultan,† Yumiko Nakajima,‡
Toshimichi Ohmura,*,§ Kazuhiko Sato,*,‡ Hayato Tsurugi,*,† Michinori Suginome,*,§
and Kazushi Mashima*,†
†Department of Chemistry, Graduate School of Engineering Science, Osaka University, Osaka 560-8531, Japan
‡Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology
(AIST), Ibaraki 305-8565, Japan
§Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510,
Japan
S
* Supporting Information
ABSTRACT: 4,4′-Bipyridyl worked as an organocatalyst for
the reduction of nitroarenes by bis(neopentylglycolato)-
diboron (B2nep2), followed by hydrolysis to give the
corresponding anilines. This reduction proceeded under
aerobic conditions without any prepurification of substrates
and reagents. We found broad functional group tolerance and
compatibility for O- and N-protecting groups under the
reaction conditions. The key in this catalytic system was the
addition of B2nep2 to 4,4′-bipyridyl to form N,N′-bis[(neopentylglycolato)boryl]-4,4′-bipyridinylidene as a deoxygenating
reagent of nitroarenes.
he deoxygenative reduction of nitroarenes is an important
Ttransformation for producing synthetically useful and
profitable aniline derivatives. Although reduction by metal
powders such as Al, Fe, Zn, In, Sn, and Sm upon combination
with any proton source such as HCl, NH4Cl, AcOH, or H2O as
well as hydrogenation catalyzed by heterogeneous catalysts
Figure 1. N,N′-Bis(trimethylsilyl)- and N,N′-bis(pinacolatoboryl)-
4,4′-bipyridinylidene.
such as Raney Ni, Pd/C, Pt/C, Rh/C, Pd/Al2O3, and Au/TiO2
are practically and industrially utilized,1,2 recent demand has
focused on high functional group tolerance to the nitro group
reduction to expand the availability of highly functionalized
the reaction of 4,4′-bipyridyl with bis(pinacolyl)diboron
(B2pin2), and the “oxidative boryl transfer” of the boryl
moieties from the 4,4′-bipyridinylidene to other heteroar-
anilines and allow for nitro group reduction in a later or final
stage in the synthesis of aniline derivatives bearing various
functional groups. In fact, various deoxygenation reactions with
omatic compounds such as pyrazine derivatives was also
demonstrated.7 A notable application of B2pin2 in the presence
of 4,4′-bipyridyl as an organocatalyst is the trans-1,2-diboration
of acetylenedicarboxylates.8 We thus focused our attention on
the reactivity of the N,N′-bis(boryl)-4,4′-bipyridinylidene
skeleton for further utilization in the deoxygenative reduction
of nitroarenes because N,N′-bis(boryl)-4,4′-bipyridinylidenes
are easily synthesized by commercially available 4,4′-bipyridyl
and diborons. Herein we report that 4,4′-bipyridyl acted as an
efficient organocatalyst for the deoxygenative reduction of
nitroarenes using bis(neopentylglycolato)diboron (B2nep2) as
a reductant under aerobic conditions without the need to
predry solvents and substrates. Control experiments revealed a
reaction mechanism in which the addition of B2nep2 to 4,4′-
bipyridyl was the key to generating an efficient deoxygenating
functional group tolerance were recently developed:3−5
A
combination of HSiCl3 and NEt3 was used for nitro group
reduction under mild reaction conditions. HSiEt3, upon
activation with B(C6F5)3, exhibits high reduction ability for
both nitroarenes and nitroalkanes, and diborons combined
with KOtBu or proton sources reduce nitroarenes under
aerobic conditions.
Recently, we reported the chemoselective deoxygenative
reduction of nitroarenes using N,N′-bis(trimethylsilyl)-4,4′-
bipyridinylidene (A) as a reductant (Figure 1). A wide range of
functional groups remained intact during single and double
deoxygenation, selectively giving N,O-bis(trimethylsilyl)-
phenylhydroxylamines and N,N-bis(trimethylsilyl)anilines.6
The corresponding pinacolatoboryl derivative, N,N′-bis-
(pinacolatoboryl)-4,4′-bipyridinylidene (B), was prepared by
Received: September 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Boron Compounds for the Reduction of Nitrobenzene (1a)
b
b
b
b
entry
1
2
3
4
5
6
reductant
conv (%)
2a (%)
entry
reductant
conv (%)
2a (%)
d
B2nep2
B2nep2
B2hex2
B2pin2
B2cat2
>99
91
3
2
83
99
93
85
3
1
4
7
B2nep2
B2nep2
B2nep2
HBpin
H3BNMe3
Me2PhSiBpin
89
49
4
8
3
89
39
n.d.
6
3
2
c
e
8
f
9
10
11
12
B2(OH)4
86
10
a
Conditions: nitrobenzene (0.40 mmol), boron compound (1.44 mmol), 4,4′-bipyridine (2 mol %, relative to nitrobenzene), CH3CN (1.5 mL),
b
100 °C, 6 h, under air in J-young nuclear magnetic resonance (NMR) tube. Determined by gas chromatography (GC) using dodecane as an
internal standard. Reaction under Ar. 1 mol % of 4,4′-bipyridyl. Reaction at room temperature for 24 h. No 4,4′-bipyridyl.
c
d
e
f
reagent for nitroarenes. In addition, N,N-diborylanilines in-
situ-generated from nitroarenes with B2nep2/4,4′-bipyridyl
were directly used to prepare ketimines upon the addition of
ketones.
substrate scope of the nitroarene reduction (Scheme 1).
para-Alkyl-substituted nitroarenes 1b,c were reduced to p-
Scheme 1. Substrate Scope for the Reduction of Nitroarenes
a
We began with searching for the best diboron to use for the
reduction of nitrobenzene (1a) in the presence of a catalytic
amount of 4,4′-bipyridyl (2 mol %), and the results are shown
in Table 1. The reaction of 1a with B2nep2 (3.6 equiv) in the
presence of a catalytic amount of 4,4′-bipyridyl (2 mol %)
under air at 100 °C for 6 h resulted in the formation of aniline
(2a) in 93% yield after hydrolysis (entry 1), whereas the yield
of 2a was slightly decreased under an argon atmosphere (entry
2). The yield of 2a was significantly affected by the substituents
on the boron atom: B2hex2 and B2pin2, with chelating diolato
substituents on the boron atom, were less effective, and 2a was
obtained in lower yield (entries 3 and 4). The treatment of 1a
with catecholato-substituted diboron, B2cat2, gave 2a in 4%
yield after workup, although the vast majority of B2cat2 was
consumed (entry 5). 4,4′-Bipyridyl also acted as a catalyst of
B2(OH)4, converting 1a to 2a in 86% yield (entry 6), although
B2(OH)4 was reported to reduce nitroarenes in water or in
organic solvents in the presence of metal catalysts.4c−e Among
the diborons we examined, B2nep2 was selected as the best for
the deoxygenative reduction of the nitro group. The yield of
B2nep2 was slightly decreased by lowering the catalyst loading
to 1 mol % (entry 7). When the reaction was carried out at
room temperature for 24 h, the yield of 2a was moderate
(entry 8). Without 4,4′-bipyridyl, 2a was not obtained (entry
9), indicating that a 4,4′-bipyridyl-activated diboron reagent
was indispensable for the initial deoxygenation (vide infra). We
also checked other boron compounds: Reactions using
hydroboranes, such as HBpin and H3B·NMe3, gave 2a in 6
and 3% yield, respectively (entries 10 and 11). Furthermore,
Me2PhSiBpin was not effective for the reduction (entry
12).9−11
by B2nep2/4,4′-bipyridyl
a
Conditions: nitrobenzene (0.40 mmol), B2nep2 (1.44 mmol), 4,4′-
bipyridyl (2 mol %, relative to nitrobenzene), CH3CN (1.5 mL), 100
°C, 6 h, under air, J-young NMR tube. Yield determined by 1H NMR
for p-substituted anilines 2b−k, by GC for 2l, and by isolation for
b
With the optimized reaction conditions in hand, including
2m−u. One mmol scale in parentheses. See the detailed procedure
4,4′-bipyridyl as the organocatalyst,12,13 we explored the
in the Supporting Information. 24 h.
c
B
DOI: 10.1021/acs.orglett.9b03419
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Organic Letters
Letter
toluidine (2b) and p-tert-butylaniline (2c) in 86 and 88% yield.
Nitroarenes 1d,e, bearing electron-donating groups at the para
position, afforded the reduced anilines 2d,e in moderate to
good yield. The reduction of nitroarenes 1f−k with electron-
withdrawing substituents at the para position proceeded
without the dehalogenation or reduction of CO and C
N moieties to give 2f−k in good to excellent yield. The
sterically congested nitroarenes 1l,m were also reduced to the
corresponding anilines 2l,m in moderate yield. In addition, a
C−C double bond was tolerated to give styrylaniline 2n in
excellent yield. When the scale-up reaction (1 mmol scale) was
conducted for 1n, the isolated yield was better under an argon
atmosphere, although the purification of reagents and the
solvent was unnecessary. The present catalytic system was
successfully applied on nitro-containing heterocycles such as
coumarin (1o), pyridine (1p), unprotected indole (1q), and a
benzofuran bearing an ester group (1r), affording 2o−r in
good yield. Nitroarenes with OH (1s), CO2H (1t), and NH2
(1u) groups on the aromatic ring were reduced to 2s−u in
moderate yield, demonstrating the stability of this catalytic
system toward protic functionalities.
alized nitroarenes, which is particularly important in multistep
synthesis.
To clarify the reaction pathway and function of 4,4′-
bipyridyl as well as B2nep2, we conducted some control
experiments (Scheme 2). The reaction of 4,4′-bipyridyl with
Scheme 2. Controlled Experiments (B =
(neopentylglycolato)boryl)
The B2nep2/4,4′-bipyridyl system showed high functional
group tolerance to various O- and N-protecting groups at the
para position of nitroarenes, which are deprotected under
acidic, basic, or hydrogenation conditions, as summarized in
Table 2. A nitro group in 1v was more reactive compared with
Table 2. Reduction of O- and N-protected Nitroarenes by
a
B2nep2/4,4′-bipyridyl
b
entry
Z
protecting group (PG)
2 (%)
1
2
3
4
5
6
7
8
O
O
O
O
NH
NH
NH
NH
C(O)Me (Ac)
2v, 84
2w, 80
2x, 62
2y, 82
2z, 80
2aa, 82
2ab, 82
2ac, 84
CH2OMe (MOM)
t
SiMe2 Bu (TBS)
CH2Ph (Bn)
C(O)OCH2Ph (Cbz)
C(O)OtBu (Boc)
C(O)Me (Ac)
S(O)2(C6H4CH3-4) (Ts)
a
Conditions: nitrobenzene (0.40 mmol), B2nep2 (1.44 mmol), 4,4′-
bipyridyl (2 mol %, relative to nitrobenzene), CH3CN (1.5 mL), 100
°C, 6 h, under air, J-young NMR tube. Isolated yield.
b
B2 nep2 at room temperature gave N,N′-bis-
[(neopentylglycolato)boryl]-4,4′-bipyridinylidene (3)
(Scheme 2a).7 The treatment of 1a with 3 (2.2 equiv) in
CD3CN at room temperature afforded N,O-bis-
{(neopentylglycolato)boryl}hydroxyaniline (4) in 92% yield
(Scheme 2b), whereas 3.6 equiv of 3 at 100 °C for 1 h
produced N-(neopentylglycolato)borylaniline-d1 (5) along
with azobenzene (6) in 30 and 11% yield, respectively
(Scheme 2c); 5 was generated by the deuteration of the
transiently generated N,N-bis{(neopentylglycolato)boryl}-
aniline by CD3CN, whereas 6 was formed by the dimerization
of the phenylnitrene derived from the thermolysis of 4 (vide
infra). In fact, the N-borylaniline (5) is the final compound
generated under the optimized reaction conditions in Table 1
before hydrolysis. When nitrosobenzene (7), a singly
deoxygenated derivative of 1a, was mixed with B2nep2 (1.1
equiv) in the absence of 4,4′-bipyridyl in C6D6 for 1 h at room
temperature, 4 was obtained in 93% yield (Scheme 2d),
the acetoxy functionality, giving 2v in 84% yield without any
deprotection (entry 1). The methoxymethyl group in 1w was
also tolerant under the reaction conditions to afford 2w in 80%
yield (entry 2). The silicon−oxygen bond in 1x and benzyl
protection in 1y remained intact for the catalyst system of
B2nep2/4,4′-bipyridyl to give 2x and 2y in 62 and 82% yield
(entries 3 and 4). In addition, carbamate moieties in 1z,aa
were retained to give 2z,aa in good yield (entries 5 and 6).
Notably, both amide and sulfonyl amide in 1ab,ac were stable
for the deoxygenation to give anilines 2ab,ac in good yield
(entries 7 and 8), although the deoxygenation of sulfoxides by
reduction using B2pin2 in the presence of a catalytic amount of
4-cyanopyridine was previously reported.13f The 4,4′-bipyridyl-
assisted diboron reduction was found to be an efficient and
superior catalyst system for the reduction of highly function-
C
DOI: 10.1021/acs.orglett.9b03419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indicating that 4,4′-bipyridyl was not necessary in the
diborylation of 7. Next, we conducted the thermolysis of 4
in the presence of B2nep2 at 100 °C in CD3CN, and 5 was
obtained as the major product, together with 6 and
azoxybenzene 8 (Scheme 2e), the latter of which was probably
formed by the reaction of 4 with in situ-generated phenyl-
nitrene along with the elimination of B2nep2. The formation of
5 in Scheme 2e suggested the involvement of 4 as the reaction
intermediate for the aniline formation. Under the optimized
reaction conditions for nitroarene reduction, the NN of 6
was partially reduced to afford 1,2-diphenylhydrazine 9 after
hydrolysis in the presence of 4,4′-bipyridyl (2 mol %)/B2nep2
(2.5 equiv) (Scheme 2f), showing a similar behavior as the
reported reduction of 6 with B2pin2 using 4-cyanopyridine as
an organocatalyst.13f To clarify the previously mentioned
arylnitrene formation by the thermolysis of 4, the reaction of 2-
phenylnitrobenzene (10) with 2.2 equiv of 3 was conducted in
C6D6 at ambient temperature for 1 h to allow the in situ
formation of N-(2-biphenyl)-N,O-bis{(neopentylglycolato)-
boryl}-2-hydroxylamine; then, the reaction mixture was heated
to 100 °C for 3 h, giving carbazole (11) in 60% yield along
with 12% of 2-aminobiphenyl (12), the former of which was
generated via the insertion of the arylnitrene into the ortho-C−
H bond (Scheme 2g).16 The effectiveness of B2nep2 among the
diborons screened (Table 1) was ascribed to the facile
thermolysis of 4 to arylnitrenes because the reaction of 7
with B2pin2 quantitatively gave N,O-bis[(pinacolato)boryl]-
hydroxyaniline, whose thermolysis with B2pin2 afforded a
complicated mixture including N-borylaniline as the only
minor product. Thus both the high deoxygenating reactivity of
3 and the facile nitrene formation from 4 were indispensable
factors in this deoxygenative reduction of nitroarenes to
anilines.
the corresponding azepin, in which C was isomerized to
benzazirine before reacting with HNEt2.14 Under the
optimized condition, C reacts with B2nep2 or 3 to give N,N-
diborylaniline D. Finally, D is basic enough to deprotonate
CH3CN, yielding N-borylaniline derivative 5. A pathway
through azobenzene (6), which is formed by the dimerization
of C, is excluded because there was no aniline formation from
6, as shown in Scheme 2f. The deoxygenation of 1a by radical
species derived from B2nep2 with 4,4′-bipyridyl is the
alternative mechanism, but it is assumed to be a minor
pathway because of the low yield of 2a for substituted pyridine
derivatives.12
The tolerance of a carbonyl group under the reduction
conditions led us to examine the reduction of 1a using B2nep2/
4,4′-bipyridyl in the presence of acetophenone at 100 °C for
16 h, affording ketimine 13a in 78% yield (Scheme 4). On the
a
Scheme 4. Ketimine Formation
a
2 equiv of acetophenone was used.
basis of a recent study for aldimine formation using N-
borylated anilines and aldehydes,15 we added acetophenone
after the formation of 5 in the reaction mixture; however, we
did not observe any formation of 13a, suggesting that the in-
situ-generated N,N-diborylaniline D was the actual iminating
reagent to ketones.16 Nitroarenes 1d and 1k, bearing para-
substituted electron-donating and electron-withdrawing
groups, afforded the imines 13d and 13k in 75 and 56%
yield, respectively. Upon the addition of 2 equiv of
acetophenone to the reaction mixture, 13k was obtained in
86% yield.
On the basis of these controlled reactions in Scheme 2, we
propose a reaction mechanism as outlined in Scheme 3. The
Scheme 3. Plausible Pathway for the Reduction of 1a by
B2nep2/4,4′-Bipyridyl (B = (neopentylglycolato)boryl)
In summary, we developed a simple protocol for reducing
nitroarenes under aerobic conditions to the corresponding
anilines by using commercially available bis-
(neopentylglycolato)diboron (B2nep2) and 4,4′-bipyridyl.
During the reduction course, we revealed that in-situ-generated
N,N′-bis[(neopentylglycolato)boryl]-4,4′-bipyridinylidene (3)
worked as an actual reactive species for the deoxygenation of
the nitro group. The superiority of B2nep2 was attributed to the
thermal instability of the in-situ-generated N,O-bis-
[(neopentylglycolato)boryl]hydroxyanilines, which decom-
posed to give the corresponding nitrenes, as trapped by
B2nep2. The advantageous point of this reduction protocol was
the high chemical tolerance to various functional groups as well
as O- and N-protecting groups. In addition, ketimines were
obtained in a one-pot manner from nitroarenes with
acetophenone under the B2nep2/4,4′-bipyridyl system without
any metal waste. Further reductive transformations of the nitro
functionality by B2nep2 with a catalytic amount of 4,4′-
bipyridyl are ongoing in our laboratories.
initial step is the deoxygenation of nitrobenzene (1a) to
nitrosobenzene (7) by 3 in-situ-generated from B2nep2 and
4,4′-bipyridyl. In this stage, 4,4′-bipyridyl functions as an
organocatalyst for the deoxygenation of 1a. The second step is
the reaction of 7 with B2nep2 or 3, giving N,O-bis-
[(neopentylglycolato)boryl]hydroxyaniline 4. The thermolysis
of 4 produces a nascent phenylnitrene C, presumably due to
the substituent effect of neopentylglycolato at the boron atom.
In fact, the thermolysis of 4 in the presence of HNEt2 afforded
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.9b03419.
D
DOI: 10.1021/acs.orglett.9b03419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental details, controlled experiment in Scheme
Letter
R. V.; Surkus, A. − E.; Junge, H.; Pohl, M.-M.; Radnik, J.; Rabeah, J.;
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Catalytic Activity and Chemoselectivity of Sub-nanometric Pd
Clusters on Porous Nanorods of CeO2 for Hydrogenation of
Nitroarenes. J. Am. Chem. Soc. 2016, 138, 2629.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ohmuraE@sbchem.kyoto-u.ac.jp (T.O.).
*E-mail: k.sato@aist.go.jp (K.S.).
*E-mail: tsurugi@chem.es.osaka-u.ac.jp (H.T.).
*E-mail: suginome@sbchem.kyoto-u.ac.jp (M.S.).
*E-mail: mashima@chem.es.osaka-u.ac.jp (K.M.).
(3) (a) Orlandi, M.; Tosi, F.; Bonsignore, M.; Benaglia, M. Metal-
Free Reduction of Aromatic and Aliphatic Nitro Compounds to
Amines: A HSiCl3-Mediated Reaction of Wide General Applicability.
Org. Lett. 2015, 17, 3941. (b) Orlandi, M.; Benaglia, M.; Tosi, F.;
Annunziata, R.; Cozzi, F. HSiCl3-Mediated Reduction of Nitro-
Derivatives to Amines: Is Tertiary Amine-Stabilized SiCl2 the Actual
Reducing Species. J. Org. Chem. 2016, 81, 3037. (c) Porwal, D.;
Oestreich, M. B(C6F5)3-Catalyzed Reduction of Aromatic and
Aliphatic Nitro Groups with Hydrosilanes. Eur. J. Org. Chem. 2016,
2016, 3307.
(4) (a) Lu, H.; Geng, Z.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Metal-Free
Reduction of Aromatic Nitro Compounds to Aromatic Amines with
B2pin2 in Isopropanol. Org. Lett. 2016, 18, 2774. (b) Yang, K.; Zhou,
F.; Kuang, Z.; Gao, G.; Driver, T. G.; Song, Q. Diborane-Mediated
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18, 4088. (c) Liu, S.; Zhou, Y.; Sui, Y.; Liu, H.; Zhou, H. B2(OH)4-
mediated One-pot Synthesis of Tetrahydroquinoxalines from 2-
Amino(nitro)anilines and 1,2-Dicarbonyl Compounds in Water. Org.
Chem. Front. 2017, 4, 2175. (d) Zhou, Y.; Zhou, H.; Liu, S.; Pi, D.;
Shen, G. Water as a Hydrogen Source in Palladium-catalyzed
Reduction and Reductive Amination of Nitroarenes Mediated by
Diboronic Acid. Tetrahedron 2017, 73, 3898. (e) Pi, D.; Zhou, H.;
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ORCID
Yumiko Nakajima: 0000-0001-6813-8733
Toshimichi Ohmura: 0000-0002-2534-3769
Hayato Tsurugi: 0000-0003-2942-7705
Michinori Suginome: 0000-0003-3023-2219
Kazushi Mashima: 0000-0002-1316-2995
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.C.M.C. acknowledges the financial support by the JSPS
Postdoctoral Fellowships (P18336). I.S. acknowledges the
scholarship from JICA Innovative Asia Program (D1805473).
This work was supported by JSPS KAKENHI grant nos.
JP15H05808 to K.M., JP15H05811 to M.S., JP18H04280 to
Y.N. (Precisely Designed Catalysis with Customized Scaffold-
ing), and JP18H01986 to Y.N. (Grant-in-Aid for Scientific
Research (B)).
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Mashima, K. Metal-Free Deoxygenation and Reductive Disilylation of
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(7) (a) Oshima, K.; Ohmura, T.; Suginome, M. Dearomatizing
Conversion of Pyrazines to 1,4-Dihydropyrazine Derivatives via
Transition-metal-free Diboration, Silaboration, and Hydroboration.
Chem. Commun. 2012, 48, 8571. (b) Ohmura, T.; Morimasa, Y.;
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F
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