A Co2B Mediated NaBH4 Reduction Protocol Applicable to a Selection of Functional Groups in Organic Synthesis

Article abstract of DOI:10.1002/ejoc.201800440

A high-yielding and high-rate reduction method that operates with alkenes, alkynes, azides, nitriles, and nitroarenes was developed and optimized. The method makes use of sodium borohydride reduction of CoSO₄ under release of hydrogen along with the formation of Co₂B as a nanoparticle material. The produced Co₂B activates the various functional groups for hydride reduction. The protocol was proven to operate with an assortment of functional groups to provide good to excellent yields. Furthermore, the reduction method was successfully adapted, implemented, and developed for a continuous flow approach using the multi-jet oscillating disk (MJOD) flow reactor platform at atmospheric pressure.

Full text of DOI:10.1002/ejoc.201800440

A Journal of
Accepted Article
Title: A Co₂B mediated NaBH4 reduction protocol applicable for a
selection of functional groups in organic synthesis
Authors: Vijayaragavan Elumalai, Frida Johanne Lundevall, Audun
Drageset, Christian Totland, and Hans-René Bjørsvik
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800440
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
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European Journal of Organic Chemistry - ejoc.201800440
A Co2B mediated NaBH4 reduction protocol applicable
for a selection of functional groups in organic synthesis
Vijayaragavan Elumalai, Frida Johanne Lundevall, Audun Drageset,
Christian Totland, and Hans-René Bjørsvik*
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
eMail: hans.bjorsvik@kj.uib.no, phone: +47 55 58 34 52, web: http://folk.uib.no/nkjhn/
Graphical abstract
R
NH2
R
R
NO2
R1
R2
R2
C
R
N
R1
NH2
R
CoII
NaBH4
/
R1
R2
R1
N
N N
R
NH2
R2
Text for the table of content
reduction method involving sodium borohydride and cobalt sulphate dissolved in aqueous ethanol was
A
developed and optimized. The established method reduce alkenes, alkynes, azides, nitriles, and nitroarenes at
high rate (3-10 min.) to afford good to excellent yield of the corresponding target reduction products.
Key Topic
Synthetic method – reduction.
Abstract
A high yielding and high rate reduction method that operates with alkenes, alkynes, azides, nitriles, and
nitroarenes was developed and optimized. The method makes use of sodium borohydride reduction of CoSO4
under release of hydrogen along with the formation of Co2B as a nanoparticle material. The protocol was proven
to operate with an assortment of functional groups to provide good to excellent yields. Furthermore, the reduction
method was successfully adapted, implemented, and developed for the continuous flow approach using a multi-
jet oscillating disk (MJOD) flow reactor platform at atmospheric pressure.
Introduction
Sodium borohydride is a versatile reduction reagent for applications in organic synthesis,
especially for the purpose of converting aldehydes and ketones to their corresponding
alcohols.[1] NaBH4 has also been used for inorganic redox reactions, including the reduction of
transition metal ions,[2] removal of metal ions from water solution, and preparation of fine
particles of metals and metal borides.[3] Furthermore, the sodium borohydride reduction of CoII
ions that has been explored as an approach for hydrogen storage for on-demand generation of
molecular hydrogen.[4] This later method provoked our interest because the solid sodium
borohydride possess a highly advantageous decomposition to provide molecular hydrogen, the
stoichiometry of this decomposition is described in equation (1):
(1)
4 CoCl2 + 8 NaBH4 + 18 H2O ® 2 Co2B + 8 NaCl + 25 H2 + 6 B(OH)3
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Even though a multifaceted use of sodium borohydride reduction of transition metal ions exist,
to the best of our knowledge, such reduction processes have not been used for practical
reduction purposes in organic synthesis, although some preceding reports have been
disclosed.[ 5 ] When the reduction process is conducted in a water solution of CoII salts,
approximately n(H2)/n(NaBH4)=(25´2)/(8´4)≈1.56 equivalents of hydrogen are produced
per equivalent of sodium borohydride. Hence, NaBH4 materializes as an excellent solid H2-
carrier (≈13 w/w-% H2 based on NaBH4). Moreover, the solid reaction product di-cobalt boride
(Co2B) holds certain interesting properties as a mediator. Fast mixing of the cobalt salt in water
solution with sodium borohydride produces Co2B as a nanoparticle material that possess a
huge surface area (70 m2 ´ g–1)[4c] a feature thatmight make the Co2B material to be an excellent
heterogeneous mediator.
The origin of the present study was based on several experimental obstacles we experienced in
two distinct research activities in our laboratory (see Schemes 1 and 2), as well as a more
general need for a reduction protocol that could be implemented on our in-house designed and
developed multi-jet oscillating disk (MJOD) continuous flow reactor platform.[6] Recently, we
disclosed an excellent method for the nitro group reduction,[7] although the method implied
handling of slurries (involves a slurry of finely divided indium metal powder in aqueous NH4Cl
and ethanol), which today is an operation that is very demanding in the context of flow
chemistry.[8] Our present challenge entailed the reducing 4'-chloro-2-nitro-1,1'-biphenyl 1 to
4'-chloro-[1,1'-biphenyl]-2-amine 2 (Scheme 1) under continuous flow conditions, a step we
intended to be included as an integral part of a complete continuous flow process leading to the
agrochemical Boscalid.® Operational and hassle-free feeding of slurries implemented on
currently existing continuous flow reactor platforms is still an unsolved problem. However, we
have proven that our multi-jet oscillating disk (MJOD) continuous flow reactor system can
operate with slurries that were formed inside the MJOD reactor tube.[9] This is in great contrast
to most of the other existing flow chemistry approaches that mostly based on micro channels
manufactured as reactor coils or reactor chips, which will be clogged by particulate material
present in the reaction mixtures.
NH2
NO2
Red. using In powder
Reaction time 3 h
Reaction temperature 120 oC (sealed tube)
Yield 88%
Red.
Cl
Cl
1
2
Scheme 1. Reduction of 4'-chloro-2-nitro-1,1'-biphenyl 1 to provide 4'-chloro-[1,1'-biphenyl]-2-amine 2.
We were also searching for a high rate and robust protocol that could replace an already
existing alkyne reduction protocol that we previously had implemented for the reduction
3 ® 4, Scheme 2.[10] The existing method was based on hydrogenation using the Pearlman’s
catalyst (Pd(OH)2/C) with methanol as reaction medium. This method was encumbered with
the drawback that it requested a very high purity of our substrate 4-(hept-1-yn-1-yl)-1-tosyl-
1H-imidazole 3. In the opposite case, the catalyst was poisoned and the reduction process was
completely blocked.
Therefore, our new knowledge about transition metal mediated sodium borohydride
decomposition to molecular hydrogen and transition metal boride propelled us to explore this
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10.1002/ejoc.201800440
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reduction process as a potential functional group reduction method for application in our
projects in progress.
O
CH3
Tos = .
S
Tos
Tos
O
Red. using Pearlman catalyst and H2
Reaction time 24 h
N
N
Red.
Reaction temperature 20 oC
Yield 76-84%
Very sensitive to impurities
H3C
N
N
4
H3C
3
Scheme 2. Reduction of 4-(hept-1-yn-1-yl)-1-tosyl-1H-imidazole 3 to 4-heptyl-1-tosyl-1H-imidazole 4.
Methods and Results.
Development of the NaBH4/CoII reduction method. Examination of the chemical literature for
reduction methods revealed a redox system constituted by sodium borohydride reduction of cobalt
(II) ions.[2,11] The experimental protocol for this redox system, equation (1), suggested the use of water
free CoCl2 as the cobalt ion source. This set-up appeared to be rather odd from an experimental
application point of view, since the reaction should be conducted with water as the reaction medium,
but also from a cost viewpoint, especially if the methods should be used for large-scale preparations.
Moreover, the previously reported reduction protocols show outsize quantities of the reduction
reagents relative to the substrate.
In order to examine the stoichiometry of the redox protocol, CoSO4 • 7H2O with NaBH4 were used
as the redox system. A series of experiment were performed, Figure 1. The literature reports a
composition of the reduction protocol composition to be NaBH4 (5-10 equiv.) and various cobalt
(II) salts (2 equiv.), which we attempted with our substrate 1. This operated as described to afford a
high yield of compound 2. We conducted a series of optimization experiment to determine an
optimized protocol (imply reduction of quantities of both Co-salt and sodium borohydride) that
involved the use of 4 equiv. of NaBH4 and 1 equiv. of CoSO4 • 7H2O, to achieve target molecule 2 in
quantitative yield.
Figure 1. Screening of reaction conditions for the NaBH4 / Co(II) reduction of R–NO2 1 to R–NH2 2.
In addition to the investigation of the composition of reduction protocol, Figure 1, an additional
series of experiments that included various cobalt salts with nitrobenzene as a model substrate
5, Table 1 were conducted. In summary, all the Co (II) salts operated together with NaBH4 in
water as a reductive system for nitrobenzene 5 to produce 1,2-diphenyldiazene 1-oxide 6 as
the major product and 3-(phenyldiazenyl)benzene-1-ylium 6a as a minor product. The
expected product aniline was not observed. Overall, the cobalt sulphate appeared as the best
choice compared with the other cobalt salts.
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Table 1. Screening of the reduction reaction with different cobalt counter ions.[a]
O
N
NO2
NaBH4(4 equiv.)
Co(II) (1equiv.)
N
N
N
EtOH, H2O,
0 oC rt ,10 min.
5
6
6a
Yield [%][b]
Price [€]
CoII/mol
#
Co(II) (1 eqv)
6
6a
1
2
3
4
CoSO4 7 H2O
CoCl2
Co(NO3)2 6 H2O
98
95
94
94
2
5
6
6
66.10[c]
120.37[d]
151.05[d]
154.78[c]
Co(OAc)2 4 H2O
[a] Reaction conditions: Nitrobenzene (1 mmol), CoSO4 7H2O
(1 mmol), ethanol (5 mL) and water (0.7 mL) were mixed in a round
bottom flask and cooled at 0 oC. Then NaBH4 (4 mmol) was
dissolved in ethanol (1.5 mL) and added to the flask. The reaction
mixture was gently stirred 10 min. at ambient temperature.
[b] GC yield
[c] Alfa Aesar
[d] Acros Organics
In addition, reduction of nitrobenzene 5 with recycled cobalt boride (Co2B) was attempted. The
method operated excellently at a small-scale (0.5 mmol) to afford a yield of 90% of the azoxy
product 6, Scheme 3, which encouraged us to perform a scale-up (10´) using 5 mmol of 7. The
reaction rate was reduced, namely at a reaction time of 10 min. the reduction reaction was
accomplished in a much smaller extent (only 23% yield) 8. A prolonged reaction time (60 min.)
did not improve the yield of the target molecule 8. The recycled cobalt boride appears not to be
suitable for the nitroarene reduction on a larger batch scale.
O
N
NO2
NaBH4(4 equiv.)
Co2B (recycled)
N
N
N
EtOH, H2O,
0oC rt ,10 min.
5
6 (90%)
6a (10%)
Scheme 3. Reduction of nitrobenzene using recycled Co2B (isolated from batch experiments) with fresh NaBH4 /
H2O.
We continued the screening/optimisation of the reaction conditions for the reduction protocol (Figure
1), by examining various protic solvents (Table 2). The screening revealed that ethanol and methanol
both are suitable solvent for the transformation of 2-nitrobiphenyl 7 to 2-aminobiphenyl 8 with
complete conversion in 10 min. (entry 1 & 2, Table 2) and low to moderate yield was obtained in 5
min. The method failed when n-propanol was used as reaction medium, probably due to a poor
solubility of the substrate. However, when a small quantity (20 mol%) of a phase transfer catalyst
(TBAB) was added to the reaction mixture (entry 3), a quantitative conversion of 2-nitro-biphenyl 7
using a reaction time of 20 min. was achieved. Nevertheless, the desired product 8 was obtained in
low yield with additional side products (8a & 8b). Moreover, the reaction with butanol afforded a
moderate-high conversion (76%) (entry 4) and with TBAB in 20 min. (entry 5), provided full
conversion of starting material, but the the amine product was obtained in low yield (only 40%)
together with carbazole as by product (25%).
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Table 2. Screening of the NaBH4 / Co(II) reduction of -NO2 group under various reaction mediums.
NaBH4 (4 equiv.)
CoSO4 7H2O (1equiv.)
O
H
OH
NO2
N
H
N
N
H
+
+
Solvent, H2O
0 o
C
rt
7
8
8a
Selec. (%)
8b
Yield (%)[a],[b]
#
Solvent Time
Conv.(%)
[min.]
7
8
8a 8b
8
8a 8b
1
2
MeOH
EtOH
5
10
86
100
46 40
0
0
41 36
0
0
100
0
100
0
5
10
18
100
57 26
0
0
10
100
5
0
0
0
100
0
3[c] PrOH
3[d] PrOH
5
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
39
5
26
21 34
10
5
9
10
20
96
99
33 40 17
17 55 23
32 39 16
17 54 23
4
BuOH
5
10
76
76
21 73
29 63
0
0
16 56
22 47
0
0
5[d,e] BuOH
20
100
40 23
0
40 23
0
[a] Yield measured by GC
[b] Trace amount of carbazole was observed in all the cases
[c] Repeated twice - no reaction observed
[d] 20 mol% TBAB was added
[e] In addition to 8 and 8a, 9H-carbazole was observed in a yield of 25%
The developed method for the reduction of nitro-arenes was attempted for the reduction of
styrene 9 as a model substance. The protocol operated with full conversion to ethylbenzene 10.
However, due to similar boiling points of the solvent used as reaction medium and the product,
an alternative reaction media with a lower boiling point was attempted, entry 2-3 Table 3.
Furthermore, the screening revealed a need for a short reaction time only (entry 6) and a
reduced quantity of the reducing reagent (entry 5).
Table 3. Screening of the NaBH4 / Co(II) reduction of the double bond of Ph-CH=CH2 under various reaction
mediums.
NaBH4
CoSO4 7H2O (1equiv.)
Solvent, rt
[b]
9
10
Yield [%][a]
#
Solvent
NaBH4 Time
[equiv.]
[min.]
10
1
2
3
4
5
6
7
EtOH/H2O
Et2O/H2O
4
4
4
1
2
2
2
10
10
10
10
10
3
100
nd
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
THF/H2O
100
77
100
100
100
10
[a] Yield measured by GC
[b] Reaction conditions: Styrene (1 mmol), CoSO4
7H2O (1 mmol), solvent (5 mL) and water (0.7 mL)
were mixed in a round bottom flask and cooled at
0 oC. Then NaBH4 (1-4 mmol) was added portions
wise (3-5 portions) to the flask. The reaction mixture
was gently stirred for further 3-10 min. at ambient
temperature.
Inorganic by-product precipitate from the reaction mixture. The inorganic precipitates collected
from both batch and continuous flow experiments were analysed by means of SEM, EDX, and ICP.
The SEM micrographs (Figure 2) reveals that the batch experiment (B) result in significant smaller,
near spherical micro-particles (0.35 µm), while the continuous flow experiment afforded larger (10´)
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particles (31 µm) with an elongated and edged appearance. The elongated particles occur both
individually and fused together to form either star-shaped structures or octahedrons, Figure 2(A),
which indicates a regular and crystalline molecular arrangement.
Figure 2. SEM micrographs of the inorganic precipitates from A) continuous flow experiments and B) batch
experiments.
To the best of our knowledge, synthesis of similar cobalt boride particles has not been reported
previously. The key difference in the formation of the two precipitates is that the precipitation in the
batch reduction process occurs as a two-step process, where cobalt sulphate forms a precipitate prior
to the addition of sodium borohydride. In the continuous flow experiment, the simultaneous addition
of all reactants will cause the reaction to occur without presence of the initial cobalt sulphate
precipitate.
In addition to the exploitation as a mediator in organic functional group reduction, cobalt boride might
be applied in fuel cell technologies, material science and for hydrogen storage.[4, 5] As such, the
properties of the cobalt boride formed during the continuous flow experiment can potentially prove
useful for other purposes and might be the focus of future studies.
The samples from batch and continuous flow experiments were submitted for element analysis using
EDX and ICP, which revealed presence of the elements: B, O, Co, Cu, Na, S, and traces of Ti. The
major elements were B, O, Co, and Na. The ratios between the elements are displayed in Table 4,
suggesting that the inorganic reduction take place similar as described in the literature,[4, 5, 12] where the
solid Co2B nano particles are coated by a (poly)borate layer.[12] This layer together with sodium salts as
revealed by the ICP and EDX analyses, might also explain why the isolated dry inorganic solids did not
operate as a re-cycled mediator, but also the non-pyrophoric properties of the isolated Co2B.[13]
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Table 4. Results from inductive coupled plasma (ICP) and energy-dispersive X-ray spectroscopy (EDX) analyses of
samples of the inorganic precipitates.
Molar composition
Reaction
Mode
#
ICP
S
EDX
B
Co Na
Cu
Ti
Co Na
S
O
−
−
1
2
3
4
Flow
Flow
Flow
Batch
2.8 1.0 2.8 0.5 0.01 Trace
2.7 1.0 2.6 0.5 0.01 Trace
2.7 1.0 2.5 0.5 0.01 Trace 1.0 3.5 1.1 14.4
2.1 1.0 2.7 1.1 0.01 Trace 1.0 2.6 0.7 20.2
−
−
−
−
−
−
Proposal for a reaction mechanism. Sodium borohydride only is not capable to reduce functional
groups such as nitro, alkene, and alkyne, which are some of the functional groups we have investigated
in this study. Sodium borohydride is hydrolysed at a high rate in water solution with the presence of
Co(II) ions under the formation of H2 and solid nano-sized particles of Co2B, see Equation (1) and
Figure 2.
Organic compound that possessed one of the said functional groups, were reduced at a high rate using
the NaBH4/Co(II) reductive system. In an attempt to discover whether the operating reductant was
borohydride or molecular hydrogen, some experiments were conducted: 1) under open atmosphere,
and 2) in a sealed tube (in order to keep the produced hydrogen present inside the reactor) were carried
out, see Scheme 4. Cobalt sulphate was dissolved in water whereupon a solution of sodium borohydride
was added. When the formation of hydrogen gas subsided, a solution of 2-nitro-1,1´-biphenyl dissolved
in ethanol was added to the reaction mixture. Both of experiments resulted in a conversion of <10% of
the substrate, which suggest that borohydride is needed present as the reductant. Then, a confirming
experiment using pure Co2B-Co3B (Alfa Aesar 99%, 10 mesh) was conducted. The organic substrate (2-
nitro-1,1´-biphenyl) and Co2B-Co3B were mixed in ethanol and placed under a hydrogen atmosphere
overnight at room temperature, Scheme 4. No reduction product was observed in the post-reaction
mixture, which strongly advises that borohydride should be present as the reductant.
Scheme 4. Attempt to reduce nitro group of 2-nitro-1-1´-biphenyl by hydrogenation mediated by cobalt.
RT
7
O2N
8
H2N
Co source/ Reductant/
#
Solvent Time
Reactor Conv. 7
equiv.
equiv.
1
2
3
CoSO4/1 NaBH4/4 EtOH/H2O 10 min. Sealed tube <10%
CoSO4/1 NaBH4/4 EtOH/H2O 10 min. Open flask <10%
Co2B/0.5
18 h
Flask w/
H2 supply
nd
H2
EtOH
Based on the achieved results, it is reasonable to conclude that cobalt is involved in the reduction
process to activate the organic substrate. An analogues mechanism to the LiAlH4 reduction[14] of the
nitrile group might be used as a model for the reduction process. First, the Co2B surface is doped by the
borohydride, path a) Scheme 5. The hydrolysis of the grafted hydride take place mediated by cobalt,
path b), but dissolved borohydride might also do this operation on substrate coordinated to cobalt.
The operating reduction process might proceed in a similar way, the organicsubstrate(here exemplified
by nitrile) is coordinated and activated by cobalt,[15] whereupon the hydride reduction take place at a
high rate, path c). The reaction is finished when the amine product is liberating by hydrolysis involving
water. When the Co2B mediator is saturated with -B(OH)3 groups [path c]], the access to the transition
metal coordinating sites become blocked and thus an inactivated mediator.
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Scheme 5. a) Co2B surface is doped by the borohydride. b) Proposal mechanism. Hydrolysis of sodium borohydride in
water. c) Functional group (nitrile) reduction by hydride mediated / catalysed by Co2B grafted with borohydride.
H
H
H
B
O
B
H
H
H
H
H
a)
O
NaBH4 doping
of the Co2B
surface
Co B Co
Co B Co
H2
H
OH
H
H
HO
OH
H
B
O
B
O
O
3
H
b)
Co B Co
Co B Co
Hydrolysis
caused by H2O
3H2
H
H
B
O
H
N
R
H
H
H
R
B
O
N
c)
Functional
group
Co B Co
Co B Co
reduction
OH
H H
H
H
OH
B
R
B
O
N
O
2 H2O
Co B Co
Co B Co
R
NH2
Scope and limitation of functional group reduction. A compound library that included alkene,
alkyne, azide, nitrile, and nitro in addition to a variety of electron-donating and electron-withdrawing
functional groups, were submitted for the developed reduction method(s). In general the method
afforded good to excellent yield and an overall high functional group tolerance.
The reduction of 2-nitro-1,1´-biphenyl and highly congested nitro compound afforded excellent yield
of the corresponding amines. Selective reduction of nitro compound with the presence of both bromo
and chloro substituents were tolerated and obtained the amine in excellent yield. However, a few
exceptions were observed. For example, when we utilized the optimized reduction protocol with
nitrobenzene and chloronitrobenzene, the corresponding azoxy benzenes were primarily formed in
the place of the target amines due to preferred reductive coupling of nitrobenzene in aqueous
medium.[16] However, increased amount of NaBH4 (5 equiv.) provided the expected amine in the case
with chloro-nitrobenzene as substrate.
Reduction of dinitro compounds were also challenging with this method. We investigated the method
with a series of dinitro compound using identical reaction conditions. However, only »50% of the
target diamine was observed. Attempts using increased quantities of the reduction reagent NaBH4 (8
equiv.) provided only some unidentified side-products. Synthesis of secondary amines are a
challenging reaction using the reduction of nitrile compounds. With the new reduction method,
benzonitrile was reduced to the secondary amine in excellent yield. Further trials were unsuccessful
with para-chloro and para-hydroxyl as substituents. However, the method operated with the nitro-
group in ortho position, the nitrile was reduced to expected primary amine. In addition, the nitro-
group was partially reduced to the nitroso group. Furthermore, the method selectively reduced the
nitro group into amine and ketone into secondary alcohol in the presence of nitriles. Azides were also
successfully reduced into their corresponding primary amines in excellent yields.
One of our initially challenges was to reduce the alkyne 3 to the corresponding alkane 4 (Scheme 2).
Thus, we conducted some trials to reduce the alkyne 3 using the initial reduction conditions involving
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NaBH4/CoII that we also used for the reduction of nitro-arenes. Trials were conducted successfully to
achieve target product 4 in quantitative yield. Reagent quantities appeared to be in huge surplus,
which prompted us to conduct method development with styrene 9 as model substance. Achieved
results are summarised in Table 3. The optimised method (entry #6) was then investigated with a
series of internal and terminal alkenes and alkynes. The method operated satisfactory in the presence
of carboxyl and ester groups and reduced selectively the olefins into alkanes. Alkenes containing
internal double bonds requested higher quantities of reducing reagent (4 equiv.) compared to terminal
olefins (2 equiv.), but the method did not operate with sterically hindered internal alkenes. Overall,
the trials revealed medium to excellent yields of target alkanes, see Table 5.
Table 5. Scope and limitation of the reduction system composed by CoSO4 / NaBH4 / H2O.[a]
NO2
NH2
H2N
H2N
H3CO
H3C
NH2
NH2
Cl
NH2
Br
NH2
Cl
Cl
H3C
Cl
84%[b, f]
H3CO
NH2
OH
94%
45%[b]
95%
96%[j,k]
93%
O
N
Cl
O
N
NH2
NH2
NH2
NH2
N
N
H2N
NH2
50%[b]
Cl
H2N
98%[b,c]
91%[b,c]
traces
50%[b]
50%[b]
C
N
CH2NH2
N
N
NH2
NO
NH2
NH2
NH2
H
N
91%[d]
NH2
NH2
75%[i]
OH
nd
NH2
78%[b]
NH2
94%[b,e]
Cl
H3C
OH
nd
95%[b,e]
N3
N
O
S
NH2
O
N
S
O
O
N
CH3
H3C
N
H
O
96%
81%
CH3
O
O
OH
OCH3
OCH3
OH
88%
Cl
55%
75%
82%
81%
nd
nd
O
O
O
HO
>99%[b]
56%[g]
75%[j]
84%
nd
47%
O
O
O
N
H2N
OCH3
O
N
79%
75%
75%
79%[h]
60%
74%
N
N
CH3
Si
CH3
>99%[b]
CH3
N
Ts
30%[b]
77%[b]
>99%[b]
74%[j]
[a] Reaction procedure: The substrate (1 mmol) was dissolved in ethanol or methanol (5 mL). A solution of CoSO4 · 7H2O (1 mmol)
dissolved in water (0.7 mL) was then added to the substrate in EtOH/MeOH solution. The reaction mixture was cooled at 0 oC,
whereupon NaBH4 (4 mmol) was added and leaved for gently stirring at ambient temperature for 3-10 min.
[b] Yield measured by GC
[c] 2% of diazo compound was formed
[d] Dibenzylamine was formed
[e] Selective reduction of the NO2 and C=O functional groups
[f] NaBH4 (5 equiv.) was added to the reaction mixture
[g] GC analysis shows a yield of 43% of 4-phenylbut-3-en-2-ol as a result of carbonyl reduction
[h] The corresponding trans isomer demonstrated low solubility and low yield (only10% with PTC present)
[i] Partial reduction of the nitrogroup to nitroso occurred.
[j] A similar experiment was conducted in sealed tube to achieve identical results. Details are given in supporting information.
[k] Two similar experiment were conducted in sealed tube using 10 mol-% CoSO4 · 7H2O. The first experiment was conducted by using
1 equivalent of NaBH4, which afforded a conversion of 8%. The second experiment was conducted by using 4 equivalents of NaBH4,
which afforded a conversion of 34%.
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
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European Journal of Organic Chemistry - ejoc.201800440
Reduction conducted on a continuous flow reactor platform. One of the major task of this
project was to develop a robust reduction methods applicable for the reduction of nitro-arenes
and alkynes to amines and alkanes, respectively. An additional principal task was to implement
the developed reduction methods for continuous flow operations. First and foremost, this was
relevant to the reduction of 4'-chloro-2-nitro-1,1'-biphenyl 1 to 4'-chloro-[1,1'-biphenyl]-2-
amine 2 needed for another project in progress, namely a continuous flow process for the
production of Boscalid.® [17]
In general, the established reduction method that comprise in-situ production of hydrogen and
the Co2B cannot be implemented on most of the commercially available flow reactors (micro-
reactor systems), because the tiny channels of the flow reactor will be clogged by the finely
divided Co2B solid material that is formed during the reduction reaction. Previously in our
group, we have designed and developed a flow chemistry approach that we have called multi-
jet oscillating disk (MJOD) continuous flow reactor[6] that can handle slurries formed inside the
reactor chamber. A commercially available system, the Coflore agitated cell reactor, can also
handle slurries formed during the course of reaction.[18] The Coflore agitated cell reactor flow
system utilize active mixing through lateral shaking of the reactor. The Coflore agitated cell
reactor was successfully used by Ley and collaborators for a reaction system that formed slurry
during the course of the to achieve target product in high yield and throughput. [19]
The MJOD continuous flow reactor utilizes mechanical agitation to generate turbulence
independent of the overall fluid flow in the MJOD reactor. This is achieved by means of a multi-
headed piston (can be described as a piston rod where several piston heads, which are
furnished with several jets, are mounted on the piston shaft that is inserted into reactor tube),
see Figure 3 b). This multi-headed piston is assembled of multi-jet disks that during operation
is moved in oscillating movements inside the reactor tube. The MJOD flow reactor rig have
successfully been utilized with processes where solid particles were formed during the course
of the reaction.[6, 9]
We set-out to utilize a similar flow reactor rig, where the MJOD flow reactor was configured for
the sodium borohydride and cobalt sulphate reduction, see Figure 3 a).
a)
b)
Figure 3. a) Process flow diagram of the continuous flow reduction process. b) The 3D through-cut model drawing
of the MJOD flow reactor shows the MJOD unit that is placed inside the reactor tube.
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
11
European Journal of Organic Chemistry - ejoc.201800440
NaBH4 has good solubility in water. However, it reacts a at slow rate with water to generate
hydrogen gas. The hydrolysis of NaBH4 can be lowered by using a slightly basic water solution
in the place of pure water. [20] Figure 3 a) shows the process flow diagram for the continuous
flow reduction process used herein. Reservoir R1 contains an ethanol solution of the substrate
(Table 6). R2 and R3 contain basic aquatic solution of sodium borohydride and water solution
of cobalt sulphate, respectively. The MJOD1 reactor was cooled with a heat exchanger (HE-1)
and oscillation mixing was controlled with an electric motor (O1). Reagents were pumped into
-
1
-
1
the MJOD1 reactor with their corresponding pumps [P1(14.84 mL min. ), P2(4.34 mL min. ),
-
1
P3(2.17 mL min. )]. The post-reaction mixture was filtered at filter unit F1 that was placed at
the output section of the MJOD continuous flow reactor. In this filtering operation, the by-
product cobalt boride was separated from the reaction mixture and the filtrate was collected in
reservoir R4. The continuous flow process was used for a small selection of nitro compounds
and an alkene, results Table 6. The method operated excellently for the nitro to amine
reduction. Unfortunately, the continuous flow version of the reduction method did not operate
for the reduction of olefins, which is due to the elevated pH of the reaction mixture (it is used
basic water to dissolve NaBH4 to minimize the water hydrolysis). This might be solved by
adjusting the pH of the reaction mixture after the basic borohydride solution is pumped into
the reactor.
Table 6 Scope and limitation of the reduction system composed by CoSO4 / NaBH4 / H2O developed and
implemented on the continuous flow MJOD reactor platform.[a]
Cl
NO2
NH2
Br
Cl
NH2
NH2
NH2
NH2
>98%
>98%
98%
96%
Cl
OCH3
83%
[a] NaBH4 (4 eqv.), CoSO4 (1 eqv.), EtOH / H2O, 3 min., 21 oC
Conclusion
We have developed a high yielding and fast reduction method applicable for the following
interconversions: -C=C- ® -CH2CH2-, -CºC- ® -CH2CH2-, -CN3 ® -CNH2, -CºN ® -CH2NH2,
and -NO2 ® -NH2 using sodium borohydride over cobalt(II)boride as mediator. The method
shows high functional group tolerance for both EWG and EDG present in the various substrates.
The method is compatible with the following functional groups ester, carboxylic acid, halogens,
and nitrile. We have revealed the developed reduction method as a general and practical
method for applications in organic synthesis for reduction of mentioned functional groups.
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
12
European Journal of Organic Chemistry - ejoc.201800440
Experimental section
Chemicals. All reagents and solvents were purchased commercially and used without being
purified. The post reaction mixtures were monitored by means of TLC (TLC plates Merck
Kieselgel 60 F254) and/or by means of GC-MS. The TLC plates were observed under UV light at
λ = 254 nm and λ = 365 nm. 1H and 13C NMR spectra were recorded with BrukerAV 500 MHz.
Analyses. GC analyses were performed with a capillary gas chromatograph equipped with a
fused silica column (l25 m, 0.20 mm i.d., 0.33 mm film thickness) at a helium pressure of200
kPa, split less/split injector and flame ionization detector. Mass spectra were obtained with a
GC–MS instrument, with a gas chromatograph equipped with a fused silica column (l30 m, 0.25
mm i.d., 0.25 mm film thickness) and helium as the carrier gas. 1H and 13C-NMR spectra were
recorded at ambient temperature at a frequency of 500 and 125 MHz, respectively. The chemical
shifts are reported in ppm relative to residual CHCl3 for proton (δ = 7.26 ppm) and CDCl3 for
carbon (δ = 77.0 ppm) and with DMSO-d6 for proton (δ = 2.50 ppm) and for carbon (δ = 39.0
ppm) with tetramethylsilane as an external reference.
Inorganic samples from the CoII/NaBH4 reduction process were analysed on a Thermo
Scientific™ iCAP 7600 ICP-OES Analyzer. Scanning electron microscopy (SEM) was performed
on a Zeiss Supra 55VP microscope in secondary electron imaging mode. The samples were
placed on carbon tape attached to aluminums stubs and sputter-coated with gold/palladium.
The MJOD continuous flow reactor platform. The MJOD continuous flow reactor is constructed
of two stainless steel tubes placed in the vertical direction (length, H), where one is placed in
the center of the other. The ring shaped space formed between the two tubes (diameters D and
d, respectively) is used to circulate cooling or heating liquid that is circulated and controlled by
an heat exchanger. A multi-jet oscillating disk unit is placed in the centre of the reactor tube
(diameter d) that is comprised of a certain number N of multi-jet disks and disk spacers (N–1).
Each multi-jet disk have a number of jets NJet that acts as static mixers. The internal multi-jet
disk unit is connected to a cam wheel driven by an electric motor where the amplitude A and
oscillating frequency f can be adjusted, which afford flexible and active mixing capabilities. The
reactants are pumped at pre-programed flow rates from adjacent reservoirs achieving desired
reactant ratios and reactor residence time. One-way valves are incorporated into the feeding
lines in order to prevent kick-back to the feeding pumps from the oscillating pressure of the
MJOD flow reactor unit. Specification for the MJOD reactor are provided in Figure 4.
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
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European Journal of Organic Chemistry - ejoc.201800440
Figure 4. Specifications of the MJOD continuous flow reactor.
Reduction of the nitro group. The nitro compound 1 (119 mg, 0.51 mmol) was dissolved in
ethanol (5 mL). To the stirred solution, CoSO4 • 7H2O (143 mg, 0.51 mmol) dissolved in water
(0.7 mL) was added. The reaction mixture was cooled at 0 oC and then NaBH4 (77 mg, 2.04
mmol) was added slowly and instantly observed the black granular precipitate (Co2B)
concomitant with gas (H2) was evolved. The reaction mixture was stirred at ambient
temperature for 10 min. After the reaction time, the reaction mixture was quenched with water
(15 mL) and filtered using Büchner funnel to remove the precipitate. The filtered solution was
diluted with EtOAc (50 mL) and washed with water (50 mL). The aqueous phase was then
extracted with EtOAc (2×40 mL). The organic phase was combined and dried over sodium
sulfate, the drying agent was filtered off and the solvent was evaporated under reduced
pressure to obtain the amine compound (2) in a yield of 95%.
Reduction of azide and nitrile. Identical to the nitro reduction protocol.
Hydrogenation of terminal alkenes and alkyne. The alkene or alkyne (1 mmol) was transferred
to a round bottom flask (25 mL) whereupon the alkene/alkyne was dissolved in methanol (5 mL).
Then CoSO4 • 7H2O (1 mmol, 281 mg) in H2O (0.7 mL) was added to the reaction flask, whereupon
o
the reaction mixture was cooled at 0 C and NaBH4 (2 mmol, 76 mg) was added as portions (5-6)
over a period of 1-2 min. The reaction mixture was further stirred for 3 min. at ambient temperature.
The post reaction mixture was filtered and washed with Et2O (2 ´ 10 mL). The filtrate was transferred
to a separatory funnel, where additional Et2O (20 mL) was added together with H2O (50 mL). After
shaking, the two phases were allowed to separate. The aqueous phase was further extracted with Et2O
(2 ´ 40 mL). The organic phases were combined and dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to obtain the corresponding alkane.
Hydrogenation of internal alkenes and alkynes. The alkene or alkyne (1 mmol) was transferred
to a round bottom flask (25 mL) whereupon alkene/alkyne was dissolved in methanol (5 mL). Then
CoSO4 • 7H2O (1 mmol, 281 mg) in H2O (0.7 ml) was added to the solution. The reaction mixture
o
was cooled to 0 C, and NaBH4 (4 mmol, 151 mg) was added portion wise (9-10 portions over a
period of 1-2 min.). The reaction mixture was further stirred for 3 min. at ambient temperature. The
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
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European Journal of Organic Chemistry - ejoc.201800440
reaction mixture was filtered and washed with Et2O (2 ´ 10 mL). The filtrate was transferred to a
separatory funnel, and Et2O (20 mL) and H2O (50 mL) were added. The phases were separated, and
the aqueous phase was extracted with Et2O (2 ´ 40 ml). The organic phases were combined and dried
over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the alkane
compound.
Scaled-up (5 mmol) hydrogenation of internal alkenes
Alkene (5 mmol) was dissolved in methanol (25 mL). CoSO4 · 7H2O (5 mmol, 1.41 g) in H2O (3.5
mL) was added to the solution. The reaction mixture was cooled to 0 oC, and NaBH4 (20 mmol, 756
mg) was added portion wise (9-10 portions over a period of 1-2 min.). The reaction mixture was
stirred for 3 min. at ambient temperature. The reaction mixture was filtered and washed with Et2O (3
´ 10 mL). The filtrate was transferred to a separatory funnel, and Et2O (100 mL) and H2O (120 mL)
were added. The phases were separated, and the aqueous phase was further extracted with Et2O (2 ´
100 mL). The organic phases were combined and dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to obtain the alkane.
Flow synthesis processes using the MJOD flow reactor.
General procedure, reduction of nitrocompounds. The MJOD flow reactor was temperature
regulated at 21 °C (HE-1) and the oscillator (O2) fixed at a frequency of f=3 Hz. 4'-chloro-2-
nitro-1,1'-biphenyl (10 mmol, 2.33 g) was dissolved in ethanol (100 mL) and transferred to
reservoir R1. NaBH4 (40 mmol, 1.52 g) was dissolved in a 0.3 M NaOH solution (30 mL) and
transferred to reservoir R2. CoSO4 · 7H2O was dissolved in water (15 mL) and transferred to
reservoir R3. The reagent reservoirs was connected to their corresponding pumps (P1-P3)
whereupon the reaction solutions were pumped into the MJOD flow reactor to provide a
residence time of t=3 min. (actual pumping rates: P1 = 14.48 mL min-1, P2 = 4.34 mL min-1, P3
= 2.17 mL min-1). The crude reaction mixture was continuously filtered on the batch filtered
(F1) at the reactor outlet. Co2B was filtered off as a solid, while the filtrate was collected in
reservoir R4. The crude reaction mixture (R4) was analysed on GC-MS revealing a quantitative
conversion into target product. The filtered post-reaction mixture of reservoir R4 was
crystallized overnight followed by a filtration. Isolated product was air dried, The isolated yield
of reduction product 4'-chloro-[1’,1-biphenyl]-2-amino was (8.8 mmol, 1.83 g, purity, 79% GC-
MS).
General procedure, reduction of olefins. The MJOD flow reactor was temperature regulated
at 21 °C (HE-1) and the oscillator (O2) was fixed at a frequency of f=3 Hz. 1-Methyl-4-(prop-1-
en-1-yl)benzene (10 mmol, 1.48 g) was dissolved in ethanol (100 mL) and transferred to
reservoir R1. NaBH4 (60 mmol, 2.28 g) was dissolved in a water (30 mL) and transferred to
reservoir R2. CoSO4 · 7H2O was dissolved in water (15 mL) and transferred to the reservoir R3.
The reagent reservoirs was connected to their corresponding pumps (P1-P3) and pumped into
the MJOD reactor to provide a residence time of 3 min. (actual pumping rates: P1 = 14.48 mL
min-1, P2 = 4.34 mL min-1, P3 = 2.17 mL min-1). The crude reaction mixture was filtered at the
batch filter F1 that was placed at the MJOD reactor outlet to remove the solid Co2B. The filtered
post-reaction mixture was collected on reservoir R4. The post-reaction mixture was analyzed
by GC-MS revealing a yield = 83% of target product.
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10.1002/ejoc.201800440
European Journal of Organic Chemistry
Accepted Article
15
European Journal of Organic Chemistry - ejoc.201800440
Analysis of the inorganic precipitate. A black colored precipitate formed during the
continuous flow reduction process was isolated by filtration and dried in open air. Three
solutions of dissolved precipitate were prepared. Samples of the precipitate (Co2B) (71 mg, 135
mg, and 200 mg) was prepared in metal free polyprofene tubes and dissolved in distilled conc.
HNO3 (2 mL). The acidic solution was diluted using distilled water (8 mL) under good agitation.
A sample (1 mL) of the diluted solution was transferred to a new clean polymer vessel
containing distilled water (9 mL), which results in a 2% HNO3 aqueous solution with a
concentration of 0.7 mg/mL, 1.35 mg/mL or 2.00 mg/mL of the collected precipitate. The
prepared solution was analysed on ICP.
Acknowledgement
V.E., F.J.L. and A.D. gratefully acknowledge the Department of Chemistry at the University of
Bergen for funding their research fellowships. Siv Hjorth Dundas and Hildegunn Almelid at
Department of Earth Science at the University of Bergen is acknowledged for excellent
assistance with ICP analyses.
Keywords: Synthetic methods · Sodium borohydride · Reduction · Cobalt · Flow Chemistry
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