Catalyst- And solvent-free efficient access to: N -alkylated amines via reductive amination using HBpin

Article abstract of DOI:10.1039/d0ob00740d

A sustainable approach which works under catalyst- and solvent-free conditions for the synthesis of structurally diverse secondary amines has been uncovered. This one-pot protocol works efficiently at room temperature and is compatible with a wide range of sterically and electronically diverse aldehydes and primary amines. Notably, this simple process offers scalability, excellent functional group tolerance, chemoselectivity, and is also effective at the synthesis of biologically relevant molecules. This journal is

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DOI: 10.1039/D0OB00740D
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Catalyst- and Solvent-Free Efficient Access to N-Alkylated Amines
via Reductive Amination using HBpin
Received 00th January 20xx,
Accepted 00th January 20xx
Vipin K. Pandey, Somnath Bauri, and Arnab Rit*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A sustainable approach which works under catalyst- and solvent- as poor selectivity, generation of toxic byproducts, need of acidic
free conditions for the synthesis of structurally diverse secondary medium and longer reaction duration.4,5c These limitations
amines has been uncovered. This one-pot protocol works efficiently compelled the researchers to develop environment-friendly,
at room temperature and compatible with a wide range of sterically economic, and modest catalytic systems for the reductive amination
and electronically diverse aldehydes and primary amines. Notably, process which is applicable to a broad range of substrates. As a
this simple process offers scalability, excellent functional group result, some metal-free N-alkylation reactions were evolved with
tolerance, chemoselectivity, and is also effective for the synthesis reductants such as hydrosilatrane, Hantzsch ester, boranes etc.
of biologically relevant molecules.
(Scheme 1a),8 however, these methods also have certain demerits as
they demand longer reaction duration and/or higher reaction
temperature, additives, tedious purification methods etc.7c,8
Recently, Ogoshi and co-workers have introduced a Frustrated Lewis
Pair (FLP) system in the reductive amination (Scheme 1a) of poly-
functionalized amines and aldehydes however, still using H2
(practically inconvenient) and elevated reaction temperature.9
The widespread applications of the amines and their derivatives in
natural products, pharmaceuticals, agrochemicals, dyes, and
polymers have raised their demands globally.1 Thus, developing
more improved and efficient protocols to access the amine related
compounds is a much demanding research area in synthetic
chemistry. Several methods have been devised to access variety of
N-alkylated amines such as nitrile reduction,2a Buchwald-Hartwig
amination,2b alkylation of amine using alcohol,2c,d and the direct
reductive amination (DRA).2a,3 Among the above mentioned
protocols, the direct reductive amination of aldehydes is the most
acknowledged method for the synthesis of higher N-alkylated
amines. This is due to the several advantages offered by this method
over others such as milder reaction conditions, utilization of the
readily available and affordable substrates, compatibility with
various functionalities, simple experimental procedures etc.3 Since
the introduction, with the passage of time, reductive amination
process has witnessed several modifications and upgradations.4
Catalytic hydrogenation using H2 and the use of reducing agents such
as borohydrides are the two most familiar ways of performing the
reductive amination (Scheme 1a).3,5a,b-c Several reports are available
based on the precious transition metals (Rh, Ru, Ir)6 driven reductive
amination reactions involving catalytic hydrogenation pathway.5a,6
However, the efficacy of this method is somewhat restricted as it is
not compatible with the multifunctional substrates featuring
unsaturated and other reducible functionalities such as nitro, cyano
and furyl groups.7 On the other hand, the commonly employed
borohydride based reducing agents also have several limitations such
a) Previous work
:
Transition metal
[Rh], [Ir], [Ru], [Au], [Fe], [Re], [Co], and [Zn]
CHO
NH2
Borohydride derivatives
N
R1
Hydrogen donor
H
R1
R
Silanes, formates and Hantzsch esters
R
Frustrated Lewis Pair (FLP)
b) This work:
H
H
catalyst-free
NH2
R2
R2
N
H
R1
R1
O
solvent-free, RT
HBpin
Catalyst- and solvent-free approach
Room temperature reaction; wide substrate scope (>40 compounds)
Biologically relevant compounds
Excellent functional group tolerance and chemoselective
Scheme 1 Overview of the prior reductive amination and this work.
In recent years, catalyst- and/or solvent-free reactions involving
diverse unsaturated functionalities such as carbonyls, carboxylic
acid, imines etc., pioneered by the hydroboration of alkenes and
alkynes, have gained enormous attention among the researchers.10
This is mainly driven by the fact that a solvent as well as catalyst-free
approach makes any process practically more convenient and
greener by avoiding the use of organic solvents and minimizing the
waste generation.11 In line with these efforts, we delved ourselves in
developing solvent- and catalyst-free mild reductive amination
approaches. Herein, we present a one-pot catalyst- and solvent-free
room temperature protocol to access diverse secondary amines via
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036,
India. E-mail: arnabrit@iitm.ac.in
Electronic Supplementary Information (ESI) available: Experimental details,
characterization data, NMR spectra of the synthesized compounds. See
DOI: 10.1039/x0xx00000x
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reductive amination using HBpin which offers impressive functional and it should be noted that our simple protocol is more effective for
group tolerance as well as the compatibility to access a range of the synthesis of 3la than the previous reports on VtiheweAcrtaictlealOynsleinde
DOI: 10.1039/D0OB00740D
biologically relevant amines.
reactions which demand higher catalyst loadings, organic solvents,
To find out the feasibility of reductive amination using HBpin, the and in addition, higher temperature and/or longer reaction time.9,12
reaction of benzaldehyde with aniline was chosen as a model The picolyl substituted amine 3ha was obtained in moderate yield.
reaction. The reaction under neat condition using 1.1 equiv. of HBpin Polyaromatic aldehyde naphthaldehyde (3m) is also compatible with
at room temperature (entry 1; Table 1) led to the direct formation of our methodology as exemplified by the isolation of 3ma and 3mb,
N-benzylaniline in 74% yield. N-benzylaniline is obtained as the end however, p-OMe substituted aniline requires longer reaction time
product possibly via hydrolysis of the imine hydroboration product than aniline to have comparable yield of the secondary amine.
by H2O, produced during the generation of the N-benzylideneaniline
from aniline and benzaldehyde. To our delight, the use of 1.3 equiv. Table 2 Substrate scope for the reductive amination reaction a
H
HBpin delivered the N-benzylaniline in excellent yield of 91% (entry
H
R2
catalyst-free
NH2
R1
R2
N
H
R1
2) which, however, slightly reduced to 84% in the absence of
molecular sieves (entry 3). Reaction at higher temperature (60 C) by
reducing the reaction duration was not helpful (entry 7). Further, the
reactions in organic solvents (entries 4-6) delivered the N-
benzylaniline in rather less yields of 82-87%. On the basis of these
observations, reaction under neat condition using 1.3 equiv. of HBpin
was set as optimized conditions for the reductive amination reaction
at room temperature.
O
solvent-free, RT
HBpin
3xy
2y
1x
R
aldehyde variation
N
N
H
N
H
N
N
H
H
R
R = OMe,
3jc
c
3ha
(24 h, 40%)
R
R
b
3ib
(12 h, 85%)
R
3aa
R = H,
(6 h, 91%)
Cl,
(12 h, 92%)
3fa
R = Br,
Cl,
(6 h, 95%)
(6 h, 96%)
3ba
CH3,
(6 h, 96%)
(12 h, 93%)
3ga
3ca
OMe,
Ar
3da
N
H
Cl,
F,
(12 h, 95%)
NH
3ea
(6 h, 94%)
Cl
Table 1 Optimization of the reductive amination reaction a
N
H
3dd
Ar = 3,5-dimethylphenyl,
(12 h, 91%)
O
H
N
H
3la
(12 h, 87%)
Ph
HBpin
3db
4-methoxyphenyl,
(12 h, 85%)b
(12 h, 92%)
NH2
3ma
R = H,
(6 h, 96%)
Ph
S
N
H
Br
Ph
3mb
= OMe,
Ph
O
3ka
(24 h, 71%)
HN
N
H
N
H
Entry
Solvent Temperature Time (h) Yield (%)b
NH
N
3oa
(12 h, 74%)
c,d
3na
(12 h, 95%)
1c
2
-
-
-
RT
RT
RT
RT
6
6
6
6
74
91
84
82
3pa
(12 h, 72%)
HN
N
H
R
N
N
H
C
N
H
3d
4
H2
NC
O2N
3ra
(24 h, 92%)
Acetonitril
3qa
3ta
R = C3H7,
C6H11
(24 h, 80%)
(24 h, 84%)
3sa
3ua
(24 h, 60%)
(24 h, 91%)
,
e
THF
DCM
-
aniline variation
R
5
6
7
RT
RT
60 ⁰C
6
6
2
84
87
77
N
N
R
H
H
N
H
R
b
3ab
R = OMe,
(12 h, 86%)
3aj
R = OMe,
3ak
(12 h, 53%)
(12 h, 82%)
a Reaction condition: benzaldehyde (0.5 mmol), aniline (0.525 mmol), HBpin
(0.65 mmol), 6 h, molecular sieves. b All are isolated yields. c 1.1 equiv. HBpin
was used. d Without using molecular sieves.
3ac
Cl,
(12 h, 88%)
Br,
3ah
R = Me,
3ai
(12 h, 88%)
(12 h, 89%)
3ae
Me,
(12 h, 82%)
(12 h, 84%)
Cl,
3af
O
Br,
3ag
CF3,
(12 h, 83%)
H
N
O
N
H
With these optimized reaction conditions, we explored the
substrate scope of our present reductive amination protocol. We
were pleased to find that various sterically and electronically distinct
amines and aldehydes which include aliphatic, (hetero)aromatic, and
polyaromatic variants with a wide range of substituents are suitable
for this method (Table 2). Notably, reaction proceeds smoothly at
room temperature except for a few cases producing the secondary
amines in good to excellent yields. First, the potential of this process
was probed by reacting aniline with varying aldehydes. Both the
electron-withdrawing as well as -donating substituents at the para-
position of benzaldehyde (1a-e) are tolerated to provide the
corresponding mono-alkylated amines (3aa-3ea) in more than 90%
yields and importantly, our present method performs better for
these substrates than those reported for the FLP, ZnII, and Hantzsch
ester based catalytic systems which require higher reaction
temperature (60-150 ⁰C) along with higher catalyst loadings.7c,9,12a
Similarly, meta-halo substituted benzaldehydes (1f-g) also provided
the desired products (3fa-3ga) in near quantitative yields.
HN
3an
(24 h, 84%)
O
N
H
c,d
3al
(12 h, 80%)
N
H
3am
(12 h, 90%)
O
O
NO2
3aq
(24 h, 72%)
N
H
N
H
3ao
(24 h, 80%)
e
3ap
(24 h, 76%)
a Reaction condition: aldehyde (0.5 mmol), amine (0.525 mmol), HBpin
(0.65 mmol), RT, 6-24 h, all are isolated yields. b 1.5 equiv. HBpin was
used. c Reactions were performed at 60 ⁰C. d 2.3 equiv. HBpin was used.
e 0.3 mL DCM was used.
Furthermore, cinnamaldehyde (1o) and 1-methylindole-2-
carboxyaldehyde (1u) which feature alkene functionality, noted to be
intolerant towards reductive amination,13a also delivered the desired
products 3oa and 3ua, respectively in good yields (60-74%).
Gratifyingly, this approach can also be extended to the one-pot
double reductive amination process and the diamine products (3na
and 3al) could be isolated in good to excellent yields although a
slightly higher temperature of 60 ⁰C is required. Next, the present
protocol is also proved to be effective for the nucleophilic
dimethylamino substituted benzaldehyde (1p) and the mono
alkylated amine 3pa was attained in good yield. It is worth
Satisfyingly, the present protocol also enables the reductive
amination for a range of heteroaromatic aldehydes such as 2-
pyridinecarboxaldehyde (1h), 5-bromothiophene carboxaldehyde
(1k), and furfural (1l). Heteroaromatic derived secondary amines 3ka
and 3la were obtained in good yields (71-87%) at room temperature
2 | J. Name., 2012, 00, 1-3
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mentioning that N,N-dimethyl-p-toluidine rather than 3pa was only 3es, precursor for the synthesis of Retigabine (an antileptic drug
detected in the previously described FLP mediated reductive which mainly works towards the proper functioning ofVtihewe pArotictalesOsinulinme
DOI: 10.1039/D0OB00740D
amination reaction of 1p and 2a.9 Acyclic longer chain aliphatic channel in brain neurons),14c at room temperature in good yield of
aldehydes have been noted to be problematic for some of the 79% (Scheme 2). It is worth mentioning that the prior reports either
reported catalytic systems.9,13b However, our method is also suitable demand the isolation of the imine intermediate using an ion
for the relatively less reactive aliphatic aldehydes such as n- exchange resin and/or the higher reaction temperature to produce
butyraldehyde and cyclohexyl carboxaldehyde and provided the N- the 3es in comparable yield.1a,14d-e
O
alkylated anilines 3qa and 3ta, respectively at room temperature in
Et
NH2
O
NH
competing yields (80-84%) of the previous methods at higher
temperature.12 Remarkably, excellent tolerance towards the nitro
and nitrile functionality was also observed and the secondary amines
(3ra and 3sa) featuring the nitro and nitrile groups unchanged were
exclusively attained in excellent yields (91-92%) at room
temperature. Substrates featuring substituents at the phenyl rings of
both the aldehyde and aniline also operate well and the desired
secondary amines (3ib, 3jc, and 3db) were realized in excellent yields
of 85-92%.
NO2
NH2
CHO
F
NH2
NH2
NO2
ref. 14d,e
standard condition
RT
NH
NH
3es
(24 h, 79%)
F
F
Retigabine
Scheme 2 Synthesis of Retigabine.
Next, we investigated the substrate scope of the present
reductive amination protocol by varying the amine counterparts
(Table 2). Accordingly, anilines installed with both the electron-
donating and -withdrawing groups at the para-position of the N-
phenyl ring (2b-c and 2e-g) were utilized and pleasingly, a range of
secondary amines (3ab-ac and 3ae-ag) were realized in good yields.
The present protocol is found to be relatively more effective for the
synthesis of the related secondary amines with variation of the C-
phenyl ring substituents (3aa-3ea) than the N-phenyl ring
substituted variants (3ab-ac and 3ae-ag). Sterically congested
anilines such as o-toluidine (2h) and o-chloroaniline (2i) are also
active and delivered the secondary amines 3ah and 3ai, respectively
in good yields (88-89%). Satisfyingly, other sterically hindered
substrates such as 3,5-dimethylaniline (2d) and 1-naphthyl amine
(2m) can also be utilized to afford the corresponding mono-alkylated
amines (3dd and 3am, respectively) in excellent yields of 90-91%.
Further, the reaction also proceeds with the meta-substituted
anilines (3aj, 3ak). Gratifyingly, ether-functionalized 1,4-
benzodioxan-6-amine (2n) and 3,4-methylene-dioxyaniline (2o) are
also proved to be effective to provide the mono-alkylated amines
(3an and 3ao) in good yields. Notably, strongly electron-withdrawing
NO2 group substituted aniline (2p) is also compatible and the
secondary amine 3ap was attained in 76% yield. It should be noted
that 2p was previously described to provide the amine 3ap in lower
yield because of the significant amount of benzaldehyde reduction
due to less imine formation.13b 4-aminoacetophenone is also active
and the secondary amine 3aq with the ketone moiety intact was
obtained in 72% yield.
Next, to explore the chemoselectivity of the present protocol,
first, benzaldehyde, aniline, and acetophenone (in 1:1:1 ratio) were
reacted and only the formation of N-benzylaniline 3aa was observed
(Figure S1) and 86% of acetophenone was also recovered from the
reaction (Scheme 3a). This shows that the present protocol is
selective to aldehyde over ketone functionality. Similarly, the
reaction of benzaldehyde with a 1:1 mixture of aniline and
benzamide was carried out and again selectively the N-benzylaniline
was exclusively formed (Figure S2). Further, the primary amine is
preferred over the secondary one (Figure S3) as exemplified by the
isolation of N-benzylaniline in 82% yield (Scheme 3c) from the
reaction of a 1:1 mixture of aniline and N-methylaniline with
benzaldehyde.
O
O
a
0.5 mmol (
O
)
CHO
O
standard
condition
N
H
NH2
NH2
0.5 mmol
NH2
HBpin
3aa
, 82-90%
b
0.5 mmol (
)
N
H
N
0.5 mmol
H
c
0.5 mmol (
)
Scheme 3 Chemoselective reductive amination reaction. All are
isolated yields.
Satisfyingly, this protocol also works for the large scale synthesis
as demonstrated by the one-pot gram scale synthesis of N-
benzylaniline 3aa in 82% yield under the optimized conditions
(Scheme S1).
Table 3 Substrate scope for biologically relevant molecules
H
N
H
N
H
N
To understand the mechanism, a few control experiments were
carried out. Reaction of the N-benzylideneaniline (intermediate of
the reductive amination process) with HBpin at room temperature
for 6 h which results in hydroboration of the imine moiety followed
by the treatment with H2O/D2O produces the N-benzylaniline-(d),
respectively (see supporting information). This demonstrates that
H2O/D2O is capable of hydrolysing the N-Bpin bond justifying the
one-pot direct formation of N-benzylaniline via in situ hydrolysis with
H2O (produced during imine formation). Along the same line, our
standard protocol in presence of excess D2O yielded N-benzylaniline-
d (Figure S8). Further, the 11B NMR analyses (22.4/21.3 ppm)
R
3vr
(65%)
3ar
3va
(65%)
(89%)
R = H,
= Br,
3vg
(49%)
Further, we focused on the synthesis of biologically relevant
amines using our present protocol. We were pleased to observe that
various secondary amines containing either the 2-phenethylamine or
benzylamine core (frequently found in the antiobesity and
anticonvulsant drugs)14a-b can also be realized by using our mild
reductive amination approach (Table 3). Several combinations of the
phenylacetaldehyde or benzaldehyde and benzylamine or
(substituted)aniline afforded the corresponding secondary amines
(3ar-3vr) in moderate to excellent yields. The utility of our present
protocol was further showcased by the effective synthesis of amine
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indicate the presence of Bpin-OH/O(Bpin)2 in the reaction mixtures
(see supporting information).15
6
7
For selected references, see: (a) V. I. Tararov, R.VKieawdAyrrtioclve,OTn.liHne.
Riermeier and A. Börner, Chem. ComDmOuIn: 1.,0.21000390/,D108O6B70–01784608D;
(b) Z. Wu, S. Du, G. Gao, W. Yang, X. Yang, H. Huang and M.
Chang, Chem. Sci., 2019, 10, 4509–4514.
For selected references, see: (a) P. N. Rylander. Catalytic
Hydrogenation over Platinum Metals, Academic Press: New
York, 1967: p 21; (b) A. Roe and J. A. Montgomery, J. Am. Chem.
Soc., 1953, 75, 910–912; (c) Q. P. B. Nguyen and T. H. Kim,
Tetrahedron., 2013, 69, 4938–4943 and references cited there
in.
For selected references, see: (a) S. E. Varjosaari, V. Skrypai, P.
Suating, J. J. M. Hurley, A. M. D. Lio, T. M. Gilbert and M. J.
Adlera, Adv. Synth. Catal., 2017, 359, 1872–1878; (b) D.
Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter and S. Rudolph,
Org. Lett., 2006, 8, 741–744; (c) Y. Kawase, T. Yamagishi, J.-y
Kato, T. Kutsuma, T. Kataoka, T. Iwakuma and T. Yokomatsu,
Synthesis, 2014, 46, 455–464.
With the support of these preliminary studies and some reported
literatures,16 we propose a plausible mechanism of the present
protocol as follows. Both the concerted and stepwise pathways are
feasible (Scheme S2). First, the aldehyde and amine couple to
generate the imine A under the removal of H2O. In the case of
concerted pathway, attachment of H2O to HBpin in the form of a 1:1
Lewis acid-base adduct enhances the hydricity of the B-H bond16 and
thereby fostering the hydride transfer from HBpin to the imine
function in A. Then the transfer of both the hydride (from HBpin) and
hydrogen (from H2O) to the imine moiety likely via a six-membered
cyclic transition state (C)16a produces the corresponding secondary
amines under the elimination of Bpin-OH. Conversely, the imine may
also first undergo hydroboration with HBpin to yield the N-borylated
amine (B) which further gets hydrolysed by H2O presumably via a
four membered transition state (D) (Scheme S2).
8
In conclusion, we have developed an efficient catalyst- and
solvent-free room temperature reductive amination protocol which
produces the secondary amines in one-pot. Our protocol is
applicable to synthetically diverse amines, which include aliphatic,
(hetero)aromatic, and polyaromatic substrates and importantly,
provides excellent chemoselectivities (aldehyde over ketone,
primary amine over the secondary amine and amide). Furthermore,
the present protocol offers excellent functional group tolerance and
can be used to access biologically relevant compounds.
We gratefully acknowledge DST, India (Project No.
DST/INSPIRE/04/2015/002219) and IIT Madras (seed grant) for the
financial support. V. K. P. and S. B. thank the IIT Madras and UGC,
India, respectively for a research fellowship.
9
Y. Hoshimoto, T. Kinoshita, S. Hazra, M. Ohashi and S. Ogoshi,
J. Am. Chem. Soc., 2018, 140, 7292−7300.
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C. E. Tucker, J. Davidson and P. Knochel, J. Org. Chem., 1992,
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Rit, Chem. Asian J., 2019, 14, 3255–3258; (d) A. Harinath, J.
Bhattacharjee, T. K. Panda, Chem. Commun., 2019, 55, 1386–
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A. Hajra, G. V. Zyryanov, O. N. Chupakhin, V. N. Charushinb and
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Varma, ChemSusChem., 2014, 7, 24–44.
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There are no conflicts to declare.
Notes and references
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