Synthesis of tertiary amines by direct Br?nsted acid catalyzed reductive amination

Article abstract of DOI:10.1039/d0cc02955f

Tertiary amines are ubiquitous and valuable compounds in synthetic chemistry, with a wide range of applications in organocatalysis, organometallic complexes, biological processes and pharmaceutical chemistry. One of the most frequently used pathways to synthesize tertiary amines is the reductive amination reaction of carbonyl compounds. Despite developments of numerous new reductive amination methods in the past few decades, this reaction generally requires non-atom-economic processes with harsh conditions and toxic transition-metal catalysts. Herein, we report simple yet practical protocols using triflic acid as a catalyst to efficiently promote the direct reductive amination reactions of carbonyl compounds on a broad range of substrates. Applications of this new method to generate valuable heterocyclic frameworks and polyamines are also included.

Full text of DOI:10.1039/d0cc02955f

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DOI: 10.1039/D0CC02955F
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Synthesis of Tertiary Amines by Direct Brønsted Acid Catalyzed
Reductive Amination
Mohanad A. Husseina An H. Dinh,a Vien T. Huynhb and Thanh Vinh Nguyena,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previous reductive amination methods
Tertiary amines are ubiquitous and valuable compounds in
synthetic chemistry, with a wide range of applications in
organocatalysis, organometallic complexes, biological processes
and pharmaceutical chemistry. One of the most frequently used
pathways to synthesize tertiary amines is the reductive amination
reaction of carbonyl compounds. Despite developments of
numerous new reductive amination methods in the past decades,
this reaction generally requires non-atom-economic processes with
harsh conditions and toxic transition-metal catalysts. Herein we
report simple yet practical protocols using triflic acid as catalyst to
efficiently promote direct reductive amination reactions of
carbonyl compounds on a broad range of substrates. Applications
of this new method to generate valuable heterocyclic frameworks
and polyamines are also included.
R2
O
NaBXnH4-n
R3
R3
H
+
R1
N
N
R4
R2
R1
or [H] and transition-metal catalyst
R4
x
Non-atom economic
x
x
Limited substrate scope
Operationally difficult
x
Toxic/precious metal catalyst
Modified Leuckart-type reactions
R2
O
metal Lewis acid catalyst
heat
Me
Me
OHC
+
R1
N
N
R2
R1
Me
Me
x
Harsh conditions (temperature, time)
x
Limited substrate scope and efficiency
This work
R2
O
O
cat. TfOH 5 mol%
Amines are an important class of compounds in organic
chemistry and fundamental building blocks of biological
processes.1 Tertiary amines, in particular, appear in a diverse
range of naturally occurring compounds and synthetic products
such as pharmaceuticals, agrochemicals and functional
materials.2 They have also been used extensively as ligands in
organometallic complexes3 as well as organocatalysts in organic
synthesis.4 Tertiary amines can be synthesized by alkylation or
arylation reaction of ammonia or less substituted amines.5 This
method, however, often suffers from over-substitution on the
nitrogen centre.5 Another frequently used synthetic route to
tertiary amines is the reductive amination reaction of carbonyl
compounds (Scheme 1), which can potentially become a
practical process due to diverse carbonyl precursors abundantly
available from feedstock chemicals.6 In the past few decades,
there have been numerous new protocols developed to
facilitate this chemical transformation.6a,6b,7 However, they
generally involve either non-atom economic processes using
+
R1
H
N
N
R2
R1
2 equiv H2O
150 °C (neat) or 60 °C (in HFIP)
R1 = alkyl, aryl
R2 = alkyl or H
33 examples
55-99% yield
alternatively
R2
cat. TfOH 10 mol%
in HCO2Et
O
H
N
+
R1
R2
N
R1
2 equiv H2O, 100 °C
R1 = alkyl, aryl
R2 = alkyl or H
15 examples
30-83% yield
Brønsted acid catalysis
High efficiency
Broad substrate scope
Interesting complex structures
Scheme 1. Direct Brønsted acid catalysed reductive amination
excessive amounts of reductants, or harsh conditions, and the
use of transition-metal catalysts such as Ir, Cu, Ag, Au, Pd, Ru or
Rh for transfer hydrogenation reaction.6b,6c,8 Hence, more
practical and environmentally benign reductive amination
procedures are still in demand.
a. School of Chemistry, University of New South Wales, Sydney, Australia
E-mail: t.v.nguyen@unsw.edu.au
b School of Chemistry, University of Sydney, Australia
Recently, attention has been brought back to modifications of
the Leuckart reaction9 in which formic acid and its ester or
Electronic Supplementary Information (ESI) available: Experimental details,
analytical data and NMR spectra are provided. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2020
Chem. Commun., 2020, 56, 1-4 | 1
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amide derivatives are used as efficient reductants for the
reductive amination.9-10 The main drawback of Leuckart-type
reactions is that they require extremely high temperature, an
issue can potentially be addressed by using suitable catalysts
and solvents. Among those studies, N,N-dimethylformamide
(DMF) is a compound of particular interest as it acts not only as
a good solvent for the reaction but also the dimethylamino
group source, in addition to being the reductant.11 Methods
employing DMF generally work with precious transition metal
complex8f,10k,10l or metal Lewis acid catalysts,10b,12 which
facilitate the in situ hydrolysis of DMF to dimethylamine and
formic acid. The former reacts with carbonyl compounds to
form N,N-dimethyliminimum intermediates, which are reduced
by formic acid to form the target dimethylaminated products.
Thus, we believe that, in principle, a Brønsted acid should be
able to promote the same transformation. To the best of our
knowledge, however, no direct Brønsted acid catalyzed
reductive amination method has been reported, except for
some non-systematic examples with unsatisfactory outcomes in
literature.12 Herein we discuss the development of simple yet
practical protocols using triflic acid as catalyst to efficiently
promote reductive amination reactions of carbonyl compounds
on a broad range of substrates (Scheme 1). Our procedure is not
only applicable to DMF but also other formamides to form a
diverse library of tertiary amine products. Several applications
of this new method to generate valuable products such as
complex N-heterocycles and polyamines are also included in
this work.
To investigate the possibility of using a Brønsted acid to catalyze
the reductive amination of carbonyl compounds, 2-
naphthaldehyde (1a) was used as the model substrate with
DMF (2a) as the amine source, reductant and solvent. A range
of readily available Brønsted acids were tested as catalysts for
this reaction (see Table S1 in the ESI for more details)13 at 10
mol% loadings. Triflic acid, a super Brønsted acid,14 showed
superior efficiency in comparison to other acids. We
subsequently carried out optimization studies with this catalyst
(see Table S2 in the ESI for more details).13 Elevated
temperatures were required to facilitate the chemical
transformation to satisfactory outcomes within reasonable
reaction times. The reaction worked best in DMF at 150 °C with
5 mol% TfOH (see entry 1, Table 1). Two equivalents of water
were found to be sufficient to mediate the reaction, whilst
previous methods required excess amounts.12 Lowering the
catalyst loading led to longer reaction times but the overall
product yield was not significantly affected by this parameter
(see Table S2 in the ESI).13
View Article Online
DOI: 10.1039/D0CC02955F
Table 1. Optimization of NHC-promoted Appel-type reactionsa
O
O
cat. TfOH (5 mol%)
N
H
H
N
H2O (2 equiv)
Temp, time
3a
2a
1a
Entrya
Solvent
DMF (equiv)
Temp
Time (h)
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
neat
-
-
Toluene
DCE
MeCN
EtOH
TFE
HFIP
[bmim]PF6
HFIP
HFIP
HFIP
HFIP
HFIP
~ 13 (1.0 mL)
150 °C
150 °C
150 °C
120 °C
100 °C
100 °C
100 °C
100 °C
60 °C
150 °C
60 °C
60 °C
40 °C
25 °C
8
8
8
8
8
8
8
8
8
90%
39%
51%
19%
41%
37%
34%
62%
67%
64%
86%
91%
40%
21%
63%
2
5
5
5
5
5
5
5
5
5
5
5
5
5
8
24
12
24
24
96
25 °C
a Reaction conditions: catalyst TfOH (0.05 mmol), aldehyde 1a (1.0 mmol), water
(2.0 mmol) and DMF (2a) in solvent (0.5 mL) in a screw-cap 4 mL reaction vial; b
Yield of isolated product.
with comparable results to the optimal setup in DMF solvent
(entry 1, Table 1, also see Tables S2 and S3 in the ESI for more
details).13 Based on the practicality of the reaction setups, we
identified two optimal sets of conditions as in entry 1 (Table 1,
Procedure A) with DMF solvent and entry 12 (Table 1, Procedure
B) with HFIP solvent. These two procedures can be used
interchangeably with similar efficiencies, as subsequently
demonstrated in this work.
Having these optimal conditions in hand, we set out to
investigate the applicability of this TfOH-catalyzed reaction on
other carbonyl compounds. Gratifyingly, the reaction worked
very well on a diverse range of substrates (Scheme 2, top) using
DMF as solvent and amination reagent. Both Procedures A and
B proved to be practical. Aromatic aldehydes generally afforded
the corresponding benzylic tertiary amines in high to excellent
yields (3a-3n, Scheme 2, top). Electron-donating or electron-
withdrawing substituents did not seem to have any significant
effect on the reaction outcomes (3h-3n). A heteroaromatic
aldehyde also reacted smoothly to give corresponding product
in high yield (3o). Aromatic ketones are less reactive and
resulted in slightly lower product yields (3p-3r) due to side-
reactions. Reactions with aliphatic substrates seemed to be
complicated with side processes but still afforded tertiary amine
products with satisfactory outcomes (3s-3t). When d7-DMF was
used instead of normal DMF, product d7-3a was obtained in
excellent yield, confirming the reductive role of the formamide
as the deuterium ended up on the benzylic position.
In order to aim for a broader substrate scope later on where the
formamide is less readily available and cannot be used as
solvent, we also explored the effect of solvents when using DMF
only as a reactant. Many of the tested solvents resulted in lower
efficiency than DMF itself (Table 1). Interestingly, fluorinated
alcohols15 such as TFE and HFIP16 and a typical ionic liquid17
[bmim]PF6, which are known for their highly ionizing ability,
gave excellent outcomes even at lower reaction temperatures
(entries 8-12, Table 1). A quick optimization study on HFIP as
reaction solvent identified a set of conditions (entry 12, Table 1)
Other formamides18 were also examined for this triflic acid
catalyzed reductive amination reaction. Under similar reaction
conditions developed in Table 1, 1-formyl pyrrolidine (2b) and
1-formyl piperidine (2c) also reacted smoothly with aldehydes
to give the corresponding products 4 or 5 (Scheme 2, middle).
2 | Chem. Commun., 2020, 56, 1-4
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O
R2
CHO
R2
View Article Online
DOI: 10.1039/D0CC02955F
cat. TfOH 5 mol%
+
R1
N
H
N
9a
, TfOH 10 mol%
TfOH 10 mol%
R1
O
2 equiv H2O
Procedure A: 150 °C (2 as solvent), 8 h
Procedure B: 60 °C, HFIP, 12 h
NH
N
N
DMF, 100 ºC
24 h, 68%
CHO
HFIP, 60 ºC, 24 h, 86%
2
3-6
1
8a
10a
7a
2a = DMF
N
via
D
8a, ethyl formate (solv.), TfOH 10 mol%
hydride abstraction
100 ºC, 24 h
CD3
N
N
N
N
from formate
83%
CD3
11a
3b, 96% (A); 94% (B)
3a, 90% (A); 91% (B)
d7-3a, 93% (A)
3c, 71% (A); 75% (B)
R1
R2
R2
R1
CHO
N
N
TfOH 10 mol%, ethyl formate (solv.)
100 ºC (sealed tube), 24 h
N
NH
N
N
7
9
10
3g, 79% (A); 82% (B)
3f, 81% (A)
3d, 91% (A)
3e, 86% (A)
OMe
Br
N
HO
O
O
N
N
N
N
N
N
EtO
MeO
3j, 84% (A)
10a, 83%
10b, 75%
10c, 61%
NO2
OMe
3k, 78% (A)
3h, 81% (A); 73% (B)
3i, 73% (A); 68% (B)
OMe
MeO
N
N
N
N
N
N
MeO
10e, 78%
10d, 60%
S
O2N
NC
OMe
3l, 87% (A)
3o, 81% (A)
OMe
3m, 82% (A); 78% (B)
3n, 89% (A); 90% (B)
N
N
N
N
N
N
5
MeO
OMe
10h, 70%
10f, 55%
10g, 59%
N
8
N
5
Scheme 3. Reductive alkylation of tetrahydroisoquinoline with aldehydes and
3p, 60% (A); 61% (B)
3q, 57% (A); 55% (B)
3r, 71% (A)
3s, 77% (A); 82% (B) 3t, 70% (A); 73% (B)
ethylformate.
2b =
O
While N-formyl THIQ 7a could also react with benzaldehyde 9a
to produce N-benzyl THIQ 10a as expected, we discovered that
it is also possible to form 10a from a direct TfOH-catalyzed
reductive coupling reaction of 7a and 9a in ethyl formate
solvent (Scheme 3). This transformation is interesting as
reductive amination reactions mediated by ethyl formate have
never been investigated in detail in literature.6-8
Presumably, the most likely pathway for this reaction could be
that the secondary amine 7a reacted with aldehyde 9a to give
an iminium intermediate (11a). 11a could then be reduced to
the product by the formate ion generated in situ from the
hydrolysis of ethyl formate under Brønsted acid catalyzed
conditions. We cannot rule out the possibility that intermediate
8a could also be concomitantly generated in the reaction
mixture by the formylation reaction of 7a with ethyl formate
N
N
N
N
OHC
8
N
O
4a, 90% (A); 88% (B)
Br
4b, 75% (A); 73 (B)
4c, 95% (A); 90% (B)
4d, 73% (A); 75% (B)
2c =
O
O
N
N
N
N
8
OHC
N
Br
5b, 79% (A); 80% (B)
5a, 87% (A); 82% (B)
5c, 90% (A); 82% (B)
5d, 66% (A); 71% (B)
O
N
O
1 =
H
H
N
O
O
6a, 79% (A)
6b, 78% (A)
O
N
O
N
6d, 77% (A)
6c, 70% (A)
Scheme 2. Substrate scope of the TfOH-catalyzed reductive amination reaction
with DMF and other formamides.
Again, both procedures with 2b or 2c as solvents or with HFIP
worked relatively well with comparable efficiencies. Preliminary
studies with some ketones only led to very sluggish reactions
with these formamides, giving less than 50% conversion after
several days, so we did not further extend the reaction scope to
this type of substrates. Interestingly, when phthalaldehyde was
used in conjunction with mono N-substituted formamides
(Scheme 2, bottom), we observed the formation of
isoindolinone derivatives 6a-6d as major products. Presumably,
R2
R2
CHO
H
TfOH 10 mol%, ethyl formate (solv.)
100 ºC (sealed tube), 24 h
N
+
N
4,5 or 13
12
9
H
N
H
H
N
N
12b =
12a =
12c =
N
N
N
Br
Br
the reaction proceeded through
a sequential reductive
Br
4b, 63%
5b, 62%
13a, 38%
amination reaction on the first aldehyde moiety followed by the
oxidative lactamization on the second aldehyde to form the
isoindoline framework. Similar cyclization reactions have been
reported for some other Lewis acid catalytic methods.6b,6c,8c,8e
In a subsequent attempt to extend the method to the synthesis
of tetrahydroisoquinolines (THIQs), which are the backbones of
many biologically valuable compounds, we synthesized N-
formyl THIQ (compound 8a, Scheme 3). This compound was
produced via transamidation reaction of THIQ 7a with DMF,19
which was conveniently catalyzed by the same TfOH catalyst.13
N
N
N
5c, 74%
4c, 72%
13b, 63%
10 mol% TfOH
NH2
N
N
H
OHC
CHO
3
+
H2N
H
ethyl formate (s)
100 ºC, 48 h
sealed tube
n
16
15
14
> 80% monomer conversion
MW ~ 2.4 kDa
Scheme 4. Other ethyl formate promoted reductive aldehyde-amine coupling reactions
Chem. Commun., 2020, 56, 1-4 | 3
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under the same conditions.19 Either way, we were able to
produce a series of N-alkylated THIQs by reacting aromatic or
aliphatic aldehydes with N-unsubstituted THIQ (7a) in
ethylformate with 10 mol% TfOH catalyst (Scheme 3).
Furthermore, the application of these conditions on the direct
coupling reaction of other secondary amines (12a-c) and some
selected aldehydes (9) in ethyl formate also gave very
encouraging outcomes (Scheme 4), which demonstrates the
generality of this protocol. More interestingly, preliminary
studies with glutaraldehyde (14) and 1,3-diaminopropane (15)
under similar conditions showed that iterative reductive
amination reaction in ethyl formate is possible to produce PEG-
type polyamines (16, Scheme 4).13 These promising results pave
the way for a new approach to valuable polyamines, which will
be further investigated in our future work.
Guo, Y. Okamoto, M. R. Schreier, T. R. Ward andVOie.wSA.rtWicleeOnngleinre,
Eur. J. Org. Chem., 2019.
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DOI: 10.1039/D0CC02955F
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In conclusion, we report simple yet practical protocols using
triflic acid as catalyst to efficiently promote direct reductive
amination reactions of carbonyl compounds on a broad range
of substrates to produce tertiary amines. This new method can
give access to valuable heterocyclic systems such as
isoindolinones and tetrahydroisoquinolines, or can be
potentially applicable to the synthesis of polyamines.
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The authors acknowledge the Australian Research Council
(grants FT180100260 and DP200100063 to TVN) for financial
support. MAH is grateful to the Iraqi HCED for sponsoring his
Ph.D. scholarship. The authors thank A/Prof Jason Harper
(UNSW Sydney) for helpful discussions.
13. See the Supporting Information for more details.
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DOI: 10.1039/D0CC02955F
Table of Content entry:
This work
R2
O
O
cat. TfOH 5 mol%
+
R1
H
N
N
R2
R1
2 equiv H2O
150 °C (neat) or 60 °C (in HFIP)
R1 = alkyl, aryl
R2 = alkyl or H
33 examples
55-99% yield
alternatively
R2
cat. TfOH 10 mol%
in HCO2Et
O
H
N
+
R1
N
R2
R1
2 equiv H2O, 100 °C
R1 = alkyl, aryl
R2 = alkyl or H
15 examples
30-83% yield
Brønsted acid catalysis
High efficiency
Broad substrate scope
Interesting complex structures
Triflic acid efficiently promotes the reductive amination reactions of carbonyl compounds
on a broad range of substrates.