CO2-Controlled Reductive Amination Reactions with NaBH4

Article abstract of DOI:10.1002/ejoc.202001408

We report the use of CO₂ to curb the reactivity of NaBH₄ enabling its use in reductive amination reactions. CO₂ readily reacts with NaBH₄ to decrease its capacity to reduce aldehydes to alcohols while remaining able to reduce imines and iminium ions for desired alkylation reactions. The formation of NaBH(OCHO)₃ as a reducing reagent was critical to achieve the desired selectivity. A general protocol was established for C–N bond formation reactions and replacing NaBH₄ with NaBD₄ allowed for reductive amination with concomitant deuteration to be carried out.

Full text of DOI:10.1002/ejoc.202001408

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: CO2-Controlled Reductive Amination Reactions with NaBH4
Authors: Allan R Petersen, Jerik Mathew Valera Lauridsen, and Ji-
Woong Lee
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001408
Link to VoR: https://doi.org/10.1002/ejoc.202001408
01/2020

10.1002/ejoc.202001408
European Journal of Organic Chemistry
FULL PAPER
CO2-Controlled Reductive Amination Reactions with NaBH4
Allan R. Petersen, Jerik Mathew Valera Lauridsen, and Ji-Woong Lee*
Abstract: We report the use of CO2 to curb the reactivity of NaBH4
enabling its use in reductive amination reactions. CO2 readily reacts
with NaBH4 to decrease its capacity to reduce aldehydes to alcohols
while remaining able to reduce imines and iminium ions for desired
alkylation reactions. The formation of NaBH(OCHO)3 as a reducing
reagent was critical to achieve the desired selectivity. A general
protocol was established for C−N bond formation reactions and
replacing NaBH4 with NaBD4 allowed for reductive amination with
concomitant deuteration to be carried out.
(NaBH(OCHO)3) was formed instead (Scheme 1). More recently,
the reaction between NaBH4 and CO2 was revisited by Knopf and
Cummins who found that
a mixture of sodium di- and
triformatoborohydride (NaBH2(OCHO)2 and NaBH(OCHO)3
respectively) was formed when a solution of NaBH4 in CH3CN was
sparged with CO2.[14] In contrast, NaBH(OCHO)3 was the sole
product when the reaction was conducted under 300 psi of
CO2.[14] The use of NaBH4 as a reducing agent for CO2 has been
investigated in the context of CO2 capture.[15] In addition, the
reduction of CO2 by NaBH4, allows for the use of CO2 as a C1
source in the methylation and formylation of amines.[16]
Introduction
The control of chemical reactivity
– nucleophilicity,
electrophilicity, reduction potential and oxidation potential - is a
major tool in designing organic reactions. Various types of
reagents with subtle variations in chemical reactivity have been
developed to provide a potentially appropriate choice of reagents
for a certain class of substrate. Together with intensive reaction
conditions optimization, the choice of reagents is critical to
achieve the desired transformation with satisfactory yields. For
example, reductive amination reactions – versatile amination
reaction for pharmaceuticals,[1] agrochemicals, materials
synthesis - require an appropriate reducing agent to prevent the
formation of by-product by the reduction of starting material
aldehyde instead of imines.[2] Therefore, chemical reactivities of
hydride donors must be suppressed to achieve high selectivity
toward amination products.
To this end, NaBH(OAc)3 or
NaCNBH3 are common choices[3] while, NaBH4/TMSCl expands
the reaction scope by enabling the reductive amination of
electron-deficient anilines with ketones.[4] NaBH4 has the
advantage of being easy-to-handle, inexpensive, accessible, and
low molecular weight.[5] The remarkable versatility of NaBH4
allows for the reduction of sugars,[6] alkyl halides,[7] conjugated
double bonds,[8] esters[9] and acids.[10] Yet the employment of
NaBH4 by itself for reductive amination would render direct
reduction of ketones and aldehydes prior to desired imine
reduction.[11]
The reduction of CO2 to formic acid, by solutions of lithium
borohydride, was reported in 1950.[12] The yield of formate
averaged 73% of the CO2 absorbed with methanol and B2H6 also
identified among the reaction products. Subsequently, the
reaction between CO2 and solid NaBH4 was found to yield the
heteroleptic borate NaBO(O2CH)(OCH3).[13] When the reaction
was conducted in dimethyl ether, sodium triformatoborohydride
Scheme 1. Top: Reaction of CO2 with NaBH4 affording NaBH(OCHO)3, a
congener of NaBH(OAc)3. Middle: The initial discovery of CO2 as a reactivity
controller in the reductive amination of HNBn2 with 4-F-benzaldehyde. Bottom:
A general protocol for using CO2 with NaBH4 for reductive amination reactions.
Although NaBH(OCHO)3 is a congener of NaBH(OAc)3, the
use of NaBH(OCHO)3 as a reducing agent for reductive amination
has to the best of our knowledge not yet been reported. Our on-
going research program to utilize CO2 for controlling organic
reactions[17] showed promising reactivity patterns in developing
new chemical reactivity of nucleophiles while improving
(stereo)selectivity. Although, the reactivity and selectivity of
NaBH4 can conveniently be modified through the addition of
reagents or Lewis acidic metals to NaBH4, CO2 has been
overlooked for this purpose.[18] Herein we report the use of CO2
as a reactivity controller for NaBH4 for reductive amination
reactions (Scheme 1). A chemoselective reducing agent is readily
generated in situ from the reaction of NaBH4 with CO2.
[*]
Dr. A. R. Petersen, J. M. V. Lauridsen, Dr. J.-W. Lee
Department of Chemistry, Nano-Science Center
University of Copenhagen
Results and Discussion
Universitetsparken 5, Copenhagen Ø, 2100, Denmark
E-mail: jiwoong.lee@chem.ku.dk
CO2 is a stable molecule, which can be involved in various
chemical processes as an innocent by-product or as a solvent.[19]
Recent progress in CO2-mediated reactions showed elegant
mode of actions – substrate activation,[20] in situ functional group
Web: www.leegroup.dk
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001408
European Journal of Organic Chemistry
FULL PAPER
protection,[21] taking advantages of CO2: inexpensive, non-toxic,
and safe.[22] Reduction and reductive amination often suffer from
10[e]
12[f]
iPr
iPr
iPr
iPr
iPr
iPr
Bn
Bn
2
2
3
3
3
4
3
3
81
88
72
74
77
67
99
85
54
53
58
56
57
49
87
72
27
35
14
18
20
18
7
flammable gases and toxic reagent combinations to achieve
desired chemoselectivity.[2a,
23]
Therefore, we commenced our
11[e]
13[f]
investigation in reductive amination using the combination of
NaBH4 and CO2 to generate NaBH4−x(OCHO)x (where x = 0-3) in
situ which would exhibit lower reduction reactivity compared to the
parent NaBH4, thus improving chemoselectivity of the reductive
amination reaction.
Our initial investigation was based upon the reductive
amination of dibenzylamine 1a with aldehyde 2a (Scheme 1,
Table 1). Prior to the addition of the amine and the aldehyde, a
suspension of NaBH4 in THF was vigorously stirred under a N2
atmosphere for 2 hours. The reaction afforded the desired product
in 4% yield with the remaining 96% of the aldehyde being reduced
to 4-fluorobenzyl alcohol 4a (entry 1). In comparison, when the
same reaction was conducted under a CO2 atmosphere, the
desired product was obtained in 92% yield (entry 3). Further
optimizations were carried out using diisopropylamine 1b instead
14[f],[h]
15[f]
16[i]
17[j]
4
[a] Unless otherwise noted, all reactions were carried out with 1a or 1b (1.0
mmol), 2a (1.0 mmol), NaBH4 (1.1 mmol), CO2 balloon, and THF (17.5 mL)
in a 40 mL vial at room temperature for 18 h. [b] Time that NaBH4 and CO2
react before the addition of amine and aldehyde. [c] The yields were
determined by 1H NMR spectroscopy of the crude product with 1,3,5-
trimethoxybenzene as an internal standard. [d] Reaction conducted under a
N2 atmosphere. [e] Reaction time 24 h. [f] 1.1 mmol of 1a or 1b was used. [g]
1.1 mmol Bu4NBr added. [h] After 3 hours and before the addition of 1a and
2a, CO2 balloon exchanged for N2 balloon and headspace flushed. [i] AcOH
(50 mol%) was added. [j] 4Å MS 500 mg was added.
of
dibenzylamine
(entries 7-15).
Sterically
hindered
diisopropylamine was chosen as a more challenging amine for
reductive amination due to the steric hindrance, reducing the
reactivity for iminium ion formation. Here the length of pre-stirring
led to the differences in yield being more pronounced: 1 hour of
pre-stirring afforded a yield of 33% of product 3b, whereas 2 hours
of pre-stirring yielded 56% after 18 hours (entries 7 and 9).
Despite there being 19% unreacted aldehyde present, extending
the reaction time from 18 to 24 hours did not increase the yield
(entry 11). We tentatively propose that as the reaction progresses
and the amine and aldehyde concentrations decline, CO2 binding
to the amine increasingly competes with iminium ion formation,
which leads to aldehyde reduction.
The addition of acetic acid, molecular sieves (4Å), which can
promote the imine formation process, showed reasonable
conversion and yields of the reductive amination product albeit
with the lower product selectivity, highlighting that the imine
formation reaction is not limiting the reductive amination process
(entries 16 and 17).
Under optimized reaction conditions, we conducted
comparison studies with conventional reducing reagents for
reductive amination namely NaBH(OAc)3 and NaBH3CN with the
model substrates (1a and 2a). As summerized in Figure 1, high
yield of reductive amination product 3a was recorded under our
reaction conditions (NaBH4/CO2), while 1 equivalent of NaBH3CN
or NaBH(OAc)3 showed inferior conversion under otherwise
identical reaction conditions. Additional experiments with a pre-
formed imine (See supporting information) also confirmed the
superior reactivity of the combination of NaBH4/CO2 (70%
conversion) compared to NaBH(OAc)3 and NaBH3CN under N2
(2% and 50% after 18 h, respectively).
Table 1. Optimization of Reaction Conditions[a]
Entry
R =
Duration of Conversion (%)[c] Yield of 3a (%)[c] Yield 4a
100
NaBH4/CO2
pre-stir (hours)
(%)[c]
[b]
NaBH3CN
80
60
40
20
0
NaBH(OAc)3
1[d]
2
Bn
Bn
Bn
Bn
Bn
Bn
iPr
iPr
iPr
2
1
2
2
2
3
1
1
2
99
99
97
99
98
97
99
99
81
4
96
14
5
86
92
91
97
92
33
0
3
4[e]
5[f]
6[e]
7
9
1
5
0
1
2
3
4
5
6
7
67
93
25
Time (h)
8[g]
9
Figure 1. Time-dependent 19F NMR yield of product 3a with NaBH4/CO2 (red),
NaBH3CN (black) and NaBH(OA)3 (gray).
56
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10.1002/ejoc.202001408
European Journal of Organic Chemistry
FULL PAPER
affording mainly [BH(OCHO)3]− and a second formate-containing
species (Figure 2, also see Section 3 in the supporting
information). Interestingly, [BH3(OCHO)]− and [BH2(OCHO)2]−
were only observed in trace amounts along with H2, a product of
hydrolysis.
To produce the desired product involves a sequence of
reactions. Firstly, NaBH4 reacts with CO2 to produce
NaBH(OCHO)3 (vide infra). Next, amine and aldehyde are added
and react to form an imine or iminium ion. Finally, the imine is
reduced by the NaBH(OCHO)3 to afford the desired product. CO2
plays a crucial role in this sequence of reactions therefore the
affect of CO2 was considered. After 3 hours of pre-stirring,
swapping the CO2 balloon for a N2 balloon led to a higher
conversion of aldehyde, yet a lower selectivity towards product
(Table 1, entry 14). We postulate that keeping the CO2 balloon
attached ensures that as much NaBH4 as possible is converted to
NaBH(OCHO)3, this can outweigh the detrimental effect of CO2
on imine formation (Table S2, entries 2-4). Previous reports on
the reaction of NaBH4 with CO2 used polar aprotic solvents
dimethyl ether and CH3CN.[13-14] THF is the primary choice as a
solvent in reductive amination reactions, particularly with
NaBH(OAc)3.[3g, 3h] After solvent optimization (Table S1 and Table
S3) our protocol showed good performance in CH3CN, DMF and
DMSO (Tables S6 and S7). At high concentrations, DMSO
displayed high selectivity for reductive amination product 3a
(Table S3, entry 2 and Table S5, entry 1) albeit the low reactivity.
In contrast the reductive amination reaction showed higher
conversion at lower concentrations when CH3CN or THF was
used. The lower solubility of NaBH4 in THF and CH3CN compared
to that in DMSO may play a role. It is worth noting that when 1.1
eq. of Bu4NBr was added to the reductive amination reaction only
the reduction product 4a was observed (Table 1, Entry 8). As the
highest yields were achieved using THF, it became the solvent of
choice in our protocol. The amount of NaBH4, the amount of
solvent (relative to NaBH4), and the time allowed for CO2 to react
with NaBH4 (duration of pre-stir) are crucial for the selectivity and
yield by influencing the effective concentration of “controlled”
reducing reagent while reactants are in reversible iminium
formation reactions (Tables S11-S14).
Further investigations were conducted to isolate potentially
reactive species as a reducing reagent. Reacting NaBH4 with CO2
in THF, for 3 hours, followed by filtration and washing with diethyl
ether afforded a white powder. The 1H NMR spectrum in DMSO-
d6 of the product displayed two singlets at 8.23 ppm and 8.43 ppm
(Figure 2, top). The signal at 8.23 ppm was assigned to the
[BH(OCHO)3]− anion whereas the signal at 8.43 ppm was
tentatively assigned to NaB(OH)(OCHO)3 or formate.[15b] The 13
C
NMR spectrum of the product displayed two signals at 164.0 ppm
and 166.5 ppm (Figure S1), which were assigned to the
[BH(OCHO)3]− anion and
a formate-containing compound,
respectively.[15b] The 11B NMR spectrum displays a singlet at 1.4
ppm, a doublet (1J BH = 129.7 Hz) at 3.2 ppm and a broad peak at
20.2 ppm, which indicates the formation of metaborate (BO2 ),
−
[BH(OCHO)3]− and boric acid (B(OH)3) respectively (Figure
S2).[15a, 15b] By using dry diglyme as a solvent, the same material
was produced on a preparative scale by reacting NaBH4 under
8.5 bar of CO2 (Figure S3-S5). The reaction between NaBH4 and
1
HCOOH in THF led to a material with similar H and 13C NMR
spectra to those obtained from the reactions of NaBH4 and CO2
(Figures S6-S7). Taken together, the presence of metaborate and
boric acid along with the hydrogen observed in the previous
experiments suggests that the formate-containing species is
formed by hydrolysis. Using rigorously inert conditions,
analytically pure NaBH(OCHO)3 has been synthesised and fully
characterised by Knopf and Cummins.[14]
With optimized reaction conditions in our hands, we
evaluated our protocol for reductive amination reactions. Primary
and secondary alkyl amines were reacted with alkyl and aryl
aldehydes. A variety of reductive aminations were carried out to
show the versatility of the NaBH4/CO2 reagent and determine its
scope and limitation (Scheme 2). Furthermore, the amines were
isolated and purified to verify our protocol.
Figure 2. 1H NMR spectra of the reaction of NaBH4 with CO2 after 1, 2 and 3
hours and after filtration (in DMSO-d6, IS = 1,3,5-trimethoxybenzene).
To provide the insight on the “controlled” reducing reagent
Scheme 2. Scope of reductive amination. Conditions: amine (1.1 mmol),
aldehyde (1.0 mmol), NaBH4 (1.1 mmol), CO2 balloon, and THF (17.5 mL) in a
40 mL vial at room temperature for 21 h. [a] Reaction performed using amine
(0.5 mmol), aldehyde (1.1 mmol). [b] Reaction performed using NH4OAc (0.33
mmol), aldehyde (1.1 mmol).
a reaction mixture between NaBH4 and CO2 in THF was studied
1
using H NMR spectroscopy. Spectra recorded after 1, 2 and 3
hours showed that the BH4− anion was consumed within 3 hours
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10.1002/ejoc.202001408
European Journal of Organic Chemistry
FULL PAPER
another advantage: CO2 takes the role often played by N2 by
displacing air from the reaction vessel thus preventing potential
oxidation from taking place. We demonstrated selected examples
of C−N bond formation reactions, which represent the utility of the
protocol such that reductive amination using highly hindered
diisopropylamine, arylamine p-anisidine and even ammonia was
made possible.
The reductive amination of secondary alkyl amines dibenzylamine
1a and diisoproylamine 1b with aryl aldehyde 4-
fluorobenzaldehyde afforded 3a in 72% yield and 3b in 45% yield
respectively. Arylamine p-anisidine and alkyl aldehyde
hydrocinnamaldehyde afforded 3c in 66%. From the reductive
amination of morpholine and alkyl aldehyde cyclohexane
carboxaldehyde, 3d was obtained in 78% yield. All products from
the reductive amination of diethylamine and 2-naphaldehyde
were separated and analyzed. From the reaction the desired
product 3e was obtained in 57% yield. 25% of the 2-naphaldehyde
1e was recovered unreacted and 2-naphthalenemethanol 4e, the
result of direct reduction of the aldehyde, was obtained in 5%. The
ligand tris(2-pyridylmethyl)amine (TPA) was obtained in 64%
Experimental Section
General Procedure for Reductive Amination Reaction
NaBH4 (41.6 mg, 1.1 mmol) was added to a 40 mL vial containing a “cross-
shaped” stirrer bar. The vial was briefly flame-dried under a stream of N2
and allowed to cool. A CO2 balloon was attached and the headspace
flushed for 3 minutes. Dry THF (17.5 mL) was added via syringe. The white
suspension was stirred for 3 hours at 750 rpm. Amine (1.1 mmol) and
aldehyde (1.0 mmol) were added. The resultant suspension was left to stir
18 hours before being quenched with saturated NaHCO3 solution (5 mL).
The mixture was transferred to a round bottom flask and the vial washed
with H2O (5 mL) and THF (10 mL). THF was removed in vacuo and the
pressure reduced to 200 mbar at 40 °C. The resultant aqueous phase was
extracted with EtOAc (3 x 10 mL). The combined organic phase was dried
over Na2SO4, filtered and concentrated in vacuo and subjected to further
purification.
yield
(3f)
from
the
reductive
amination
of
2-
pyridinecarboxaldehyde with 2-(aminomethyl)pyridine. If instead
NH4OAc was used as a source of NH3, TPA was obtained in 29%
yield (3g). Using this protocol the reductive amination of primary
amines and even ammonia is possible. Moreover that multiple C-
N bonds can be formed in one step using our protocol,
demonstrating the versatility with primary, secondary and
arylamines with aromatic and aliphatic aldehydes.
Preliminary mechanistic studies were performed by using
sodium borodeuteride (NaBD4) in conjunction with CO2 as a
method of conducting reductive amination with concomitant
deuterium labelling (Scheme 3). Here 3a-d1 was obtained in 57%
yield confirming the hydride source is in principle from NaBH4 thus
enabling selective D-labelling with CO2.
Acknowledgements
The generous support from the Department of Chemistry,
University of Copenhagen, and from the Villum Fonden
(00019062) is gratefully acknowledged. We also thank our
analytical departments (NMR, GC/MS, LC/MS, HRMS) for their
kind support.
Scheme 3. Reductive amination with concomitant deuterium-labelling.
Keywords: reductive amination • NaBH4 • CO2 • C-N bond •
reduction
Conclusions
References
CO2 has a remarkable effect on reductive amination
reactions using NaBH4 as a pre-reducing agent. NaBH4 reacts
with CO2 to afford NaBH(OCHO)3 a congener of the well-known
reducing agent NaBH(OAc)3. Analogous to NaBH(OAc)3,
NaBH(OCHO)3 is less active than NaBH4 allowing it to
preferentially reduce imines and iminium ions in the presence of
aldehydes. Both NaBH4 and CO2 are cheap and readily available,
even on an industrial scale. As a reagent for reductive amination
reactions NaBH4/CO2 is a cheaper alternative to NaBH(OAc)3 and
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explosive H2 gas. The use of NaBH4/CO2 as the reducing agent
ensures a safe protocol. In addition, the use of CO2 as inert gas is
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10.1002/ejoc.202001408
European Journal of Organic Chemistry
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Key Topics: CO2-Mediated Synthesis
The reactivity of NaBH4 was controlled by atmospheric CO2, thus suppressing direct reduction of aldehydes to alcohols. High selectivities
towards reductive amination alkylation reactions indicate the in-situ formation of less reducing NaBH(OCHO)3. This protocol provides a
surrogate for conventional reducing reagents in reductive amination reactions.
Institute and/or researcher Twitter usernames: TheLeeLab_Chem
This article is protected by copyright. All rights reserved.