Triarylborane catalysed: N-alkylation of amines with aryl esters

Article abstract of DOI:10.1039/d0cy01339k

The ability of halogenated triarylboranes to accept a lone pair of electrons from donor substrates renders them excellent Lewis acids which can be exploited as a powerful tool in organic synthesis. Tris(pentafluorophenyl)borane has successfully demonstrated its ability to act as a metal-free catalyst for an ever-increasing range of organic transformations. Herein we report the N-alkylation reactions of a wide variety of amine substrates including diarylamines, N-methylphenyl amines, and carbazoles with aryl esters using catalytic amounts of B(C6F5)3. This mild reaction protocol gives access to N-alkylated products (35 examples) in good to excellent yields (up to 95%). The construction of a C-N bond at the propargylic position has also been demonstrated to yield synthetically useful propargyl amines. On the other hand, unsubstituted 1H-indoles and 1H-pyrroles at the C3/C2 positions afforded exclusively C-C coupled products. Extensive DFT studies have been employed to understand the mechanism for this transformation.

Full text of DOI:10.1039/d0cy01339k

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DOI: 10.1039/D0CY01339K
ARTICLE
Triarylborane Catalysed N-Alkylation of Amines with Aryl Esters
Valeria Nori,a,b Ayan Dasgupta,a* Rasool Babaahmadi,c Armando Carlone,b Alireza Ariafard,c and
Rebecca L. Melena
Received 00th January 20xx,
Accepted 00th January 20xx
The ability of halogenated triarylboranes to accept a lone pair of electrons from donor substrates renders them excellent
Lewis acids which can be exploited as a powerful tool in organic synthesis. Tris(pentafluorophenyl)borane has successfully
demonstrated its ability to act as a metal-free catalyst for an ever-increasing range of organic transformations. Herein we
report the N-alkylation reactions of a wide variety of amine substrates including diarylamines, N-methylphenyl amines,
carbazoles, 1H-indoles, and 1H-pyrroles with aryl esters using catalytic amounts of B(C6F5)3. This mild reaction protocol
gives access to N-alkylated products (35 examples) in good to excellent yields (up to 95%). The construction of C–N bond
at the propargylic position has also been demonstrated to yield synthetically useful propargyl amines. On the other hand,
unsubstituted 1H-indoles and 1H-pyrroles at the C3/C2 positions afforded exclusively C–C coupled products. Extensive
DFT studies have been employed to understand the mechanism for this transformation.
DOI: 10.1039/x0xx00000x
Introduction:
Over the last decade there has been a surge of interest in the
applications of triarylboranes as metal-free catalysts for a range
of transformations. This research originates from the seminal
work of Piers who, in 1996, demonstrated the use of
tris(pentafluorophenyl)borane [B(C6F5)3] as an effective catalyst
for the hydrosilylation of carbonyl compounds.1 A decade later
a derivative of this borane, containing a p-PMes2 functionality
on one of the aryl rings, was reported to be capable of reversibly
activating H2 in the absence of a transition metal. 2 This system,
comprising unquenched Lewis acidic and basic sites, was
subsequently termed a frustrated Lewis pair (FLP).3 These two
key findings by Piers and Stephan have altered the way chemists
think about the reactivity of triarylborane Lewis acids
prompting the discovery of new catalytic reactivity of these
boron compounds.4,5 Many researchers have investigated the
breadth of reactions B(C6F5)3 can catalyze, whereas others have
focused on catalyst modification through subtle alterations of
the aryl rings to influence the accessibility and energy of the
empty p-orbital at boron.5 One of the most studied reactions in
FLP chemistry has been the application of B(C6F5)3 (and
derivatives) for the FLP-catalyzed hydrogenation of imines to
generate amines.6,7,8 Owing to the importance of nitrogen-
Scheme 1. Amine synthesis catalyzed by triarylboranes. A) previous work on the
use of triarylboranes in reductive amination. B) This work on borane catalyzed N-
alkylation. C) Borane catalysts employed in current and previous studies.
containing compounds in nature, new synthetic methods to
develop C–N bonds in a mild and efficient manner are
continuously being sought.9 One common approach to
synthesize C–N bonds is through reductive amination, a
reaction that has been commonly mediated using transition
metal catalysts. 10,11 Several groups (including ourselves) have
employed a metal-free FLP-catalyzed strategy for reductive
amination using the Lewis acidic boranes B(C6F5)3,
a. Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building,
Park Place, Cardiff, CF10 3AT, Cymru/Wales, United Kingdom.
b. Department of Physical and Chemical Sciences, Università degli Studi dell’Aquila,
via Vetoio, 67100 L’Aquila, Italy.
c. School of Natural Sciences-Chemistry, University of Tasmania Private Bag 75,
Hobart, Tasmania 7001, Australia.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reaction conditions.
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DOI: 10.1039/D0CY01339K
Fig. 1. Solid-state structures of compound 4c (left) and 5a (right). Thermal ellipsoids
drawn at 50% probability. Carbon: black; nitrogen: blue; fluorine: green.
Entry
Catalyst
none
B(C6F5)3
BCl3
Solvent
Temperature Time Yield
(°C) (h) (%)
80 NR
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Toluene
Toluene
oluen
24
16
24
24
22
22
16
42
24
24
24
24
24
24
24
The p-fluorobenzoate esters were selected due to the ease of
reaction monitoring by 19F NMR spectroscopy.
80
80
80
80
80
110
RT
45
60
80
65
80
40
80
92
NR
5
T
e
Other boranes, including the more Lewis acidic BCl3 and less
Lewis acidic BPh3, gave little or no reaction under identical
conditions. Likewise, Brønsted acids such as triflic or p-
fluorobenzoic acid gave low or no conversion. Reaction at
higher temperature (110 °C) using 10 mol% B(C6F5)3 led to the
formation of many other small impurities and lower isolated
yields (52%) than the reaction at 80 °C. On the other hand, the
room temperature reaction showed no conversion Toluene was
found to be the best solvent for the reaction with CH2Cl2 (56%),
α,α,α-trifluorotoluene (TFT) (51%), and hexane (64%) showing
only moderate yields. In addition, the more coordinating
solvents THF (45%), Et2O (36%), and acetonitrile (25%) showed
a further reduction in yields. Reducing the catalytic loading to 5
mol% also drastically reduced the yield to just 30% after 24 h.
With the optimized conditions in hand, the substrate scope
for the reaction was investigated (Scheme 2). Initially,
BPh3
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
TFT
Hexane
Acetonitrile
Et2O
CF3SO3H
p-FC6H4CO2H
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
39
NR
52
NR
56
45
51
64
25
36
30
a
B(C6F5)3
Toluene
*yields reported are isolated yields. All reactions were carried out in 0.1 mol% scale
using 10 mol% catalyst. NR indicates no reaction. a5mol% catalyst employed
B(2,6-Cl2C6H3)(p-HC6F4)2, and B(2,6-Cl2C6H3)2(2-Cl-6-FC6H3)
(Scheme 1). In these reactions, the primary or secondary amine
is initially condensed with an aldehyde or ketone and, in the
second step, the borane catalyzes the reduction of the imine
using H212 or a silane.13 Recent studies indicate that B(C6F5)3 can
also be used as effective catalyst towards the N-alkylation of
various amines. Chan et al. reported the solvent dependent
chemoselective N-alkylation of aryl amines with alcohols using
B(C6F5)3 as a catalyst.14 Furthermore, N-alkylation of primary
and secondary aromatic amines and amides with primary,
secondary, tertiary benzylic alcohols has been demonstrated by
Maji et al. Activation of the dibenzyl ether intermediate by
triarylflurorboranes was identified as the rate determining
step.15 Here we report an alternative borane catalyzed
approach to Csp3–N bond formation through the N-alkylation of
an amine with an ester catalyzed by B(C6F5)3. Unlike the FLP
reductive amination approach, these reactions occur at lower
temperatures and do not require the use of hydrogen gas or
silane reductants. Mild reaction protocol for synthesis of
propargyl amines has also been highlighted.
secondary diaryl amines 1a
–c
were reacted with a range of
symmetrical diaryl esters 2a
–
d (see SI for details of starting
material structures and their synthesis) to generate the N-
alkylated products 3a in good to excellent yields (63–92%).
–
j
The reactions were found to be tolerant to electron
withdrawing (p-F) and electron donating (p-OMe) groups on the
ester but were generally limited to more electron rich amines.
Unsymmetrical diaryl esters 2e
products 3k in good to excellent yields (70–89%). Several
alkynyl/aryl substituted esters 2g also performed well
showing N-alkylation at the propargylic position to generate
propargyl amines 3o in 55–75% isolated yields. Indeed, the
–f also worked well giving
–n
–
i
–
q
synthesis of propargylic amines is often metal catalyzed16 and
new routes to these compounds are important owing to their
prevalence in biologically active compounds, as well as their
applications in medicinal and synthetic chemistry. Aryl/alkyl
esters 2j–l could also be employed; however, with the tert-butyl
group, the reaction provided the N-alkylated product 3s in only
21% yield. Fortunately, the efficiency of the reaction could be
restored by employing cyclohexyl and methyl substituents
Initially, we investigated the N-alkylation reaction of
diphenyl amine (1a) with p-fluorobenzoate diarylester 2a as a
model system (Table 1). In the absence of a borane catalyst no
reaction occurs in toluene. However, addition of 10 mol%
B(C6F5)3 led to C–N bond formation with elimination of p-
fluorobenzoic acid to generate the N-alkylated product 3a in
excellent isolated yields of 92% after 16 h at 80 °C.
yielding 3r
amine to have an aliphatic group was also successful and
reactions of N-methyl aniline (1d) with esters gave 3w in 71–
, t–v in 65–72% isolated yields. Likewise, changing the
–y
82% yield. Indoline (1e), on the other hand gave poorer yield for
the alkylated product 3z of 32% as calculated from crude NMR.
Limitations of this reaction included the aliphatic amines
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diisopropylamine, morpholine, and piperidine, which showed acidic boranes to afford the desired N-alkylated products. This
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DOI: 10.1039/D0CY01339K
no reaction even when elevating the temperature to 120 °C. The was also observed in NMR experiments using equimolar
higher basicity of these aliphatic amines, and the potential to mixtures of diisopropyl amine and B(C6F5)3 which showed
react with B(C6F5)3 through hydride abstraction,17 compared several reaction products in the in situ 11B NMR spectrum.
with aromatic amines makes them incompatible with the Lewis
Scheme 2. N-Alkylation reactions of amines with diaryl esters. All reactions were carried out on a 0.1 mmol scale. Yields reported are isolated yield. aCrude NMR yield
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DOI: 10.1039/D0CY01339K
Scheme 3. N-Alkylation reactions of amines with diaryl esters. All reactions were carried out on a 0.1 mmol scale. Yields reported are isolated yield. aCrude NMR yield
Scheme 4. Catalytic cycles investigated for the reaction. (i) Brønsted acid catalyzed from activation of the amine (a) or carboxylic acid (b). (ii) Lewis acid catalyzed (c).
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Fig. 2. Reaction profile for the DFT calculated mechaism at the SMD/M06-2X/def2-TZVP//CPCM/B3LYP/6-31G(d) level of theory. Bond lengths shown in Å. Relative
energies given in kcal/mol.
The primary amine, aniline, on the other hand gave a
complex mixture of products including the secondary amine
product from mono alkylation and the tertiary amine
product from double alkylation at the nitrogen atom.
Following this, we turned our attention to N-alkylation of
aromatic N-heterocycles including carbazoles and indoles
with aryl esters. N-alkyl carbazoles are an important class of
bioactive heteroaromatic compounds.18 Their synthesis
often relies on an SN2 reaction, but this is sensitive to more
hindered electrophiles, although metal catalyzed processes
have recently been reported.19 Other syntheses typically
involve heterocycle generation after incorporation of the
alkyl group at nitrogen. This includes precious metal
catalyzed routes, benzannulation or oxidative cyclization
reactions.20 We therefore sought to employ our
methodology in the synthesis of N-alkyl heterocycles. 9H-
Carbazole (1f) and 3,6-dibromo-9H-carbazole (1g) were
employed giving the products 5a–c in good to excellent
yields (64–80%) when reacted with esters bearing electron
donating or electron withdrawing groups. Suitable crystals of
4c and 5a were obtained from slow evaporation of saturated
CH2Cl2 solutions and could be characterized by single-crystal
X-ray diffraction (Fig. 1). Surprisingly, when 1H-indole (1j
)
was treated with 2a, no N-alkylated product was observed
and exclusive formation of the C–C cross-coupled product
(
6a) was isolated in excellent yield (93%). Likewise, 1H-
pyrrole (1k) also exhibited similar reactivity and the C–C
cross-coupled product (7a) was isolated exclusively in 95%
yield. In both cases, addition of further equivalents of the
ester
2 still saw no N-alkylation reaction. The generation of
the C-alkylated product is likely due to the formation of a
Lewis acid-base adduct between the indole or pyrrole and
the borane which protects the nitrogen centre from
alkylation. We have observed similar selectivity in the
reactions of these substrates with diazo esters catalyzed by
B(C6F5)3.21 Similarly, blocking all other positions as in 2,3,4,5-
tetramethyl pyrrole displayed no product formation. 2-
Oxyindole was also tested for the N-alkylation reaction with
2a but complicated mixtures of products resulted along with
reacted with esters 2a
,
b
and
d, giving excellent yields (81–
95%) of the N-alkylated products (4a
–f
). As before, the
reaction worked well with both electron donating and
electron withdrawing groups on the ester. However, when
employing electron donating groups on the amine (3,6-
dimethoxy-9H-carbazole
(
1h),
a
complicated reaction
unreacted 2a.
mixture was obtained, and the presence of unreacted
starting material was observed by TLC. The C3 and C2
substituted indole 2,3-dimethyl-1H-indole (1i) could also be
To investigate the mechanism for the N-alkylation
reaction, we undertook a series of DFT calculations. We
hypothesized that three mechanisms could be possible for
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the reaction: a Lewis acid-assisted Brønsted acid-catalyzed
reaction from activation of the amine (Scheme 3a) or the
carboxylic acid by-product (Scheme 3b), or a Lewis acid-
catalyzed reaction (Scheme 3c). In all cases, the
Lewis/Brønsted acid activates the ester generating a
carbenium species that is subsequently trapped by the
amine nucleophile. The generation of the carbenium ion
corroborates the observation that esters used in the reaction
must bear groups able to stabilize a positive charge.
Calculations into the first mechanism (Scheme 3a and ESI,
Figure S115) at the SMD/M06-2X/def2-TZVP//CPCM/
B3LYP/6-31G(d) level of theory show that the borane initially
coordinates to the amine generating an acidic proton. This
adduct formation was found to be energetically unfavorable
relative to the free Lewis acid and base by 4.4 kcal/mol
presumably due to steric hindrance. Upon coordination, the
acidity of the amine increases, however, the next step of the
reaction (protonation of the ester) had a high activation
barrier of 40.5 kcal/mol (Figure S115). An alternative
Brønsted acid catalyzed pathway could operate in which the
borane activates the 4-fluorobenzoic acid side product,
generating an acidic proton (Scheme 3b, Figure S116). As in
acid catalyzed pathway over the Brønsted acid catalyzed
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pathway. Thus, we propose that theDLOeI:w10is.10a3c9id/D0cCatYa0l1y3z3e9dK
pathway predominates in this reaction. It should be noted
that the reaction of B(C6F5)3 with carboxylic acids can
generate RCO2B(C6F5)2 and C6F5H.23 It is therefore possible
that an alternative Lewis acid catalyzed pathway could
operate with RCO2B(C6F5)2 acting as the active catalyst,
however in situ NMR studies showed little correlation
between the reaction of stoichiometric B(C6F5)3 and p-
fluorobenzoic acid and the catalytic reaction in the 19F NMR
spectrum (See ESI for details).
Lastly, we rationalized why heating is required for the
reaction to take place. We hypothesized that several off-
cycle catalyst resting states could exist. These include
coordination of the borane to the 4-fluorobenzoic acid (8)
side product which was found to lie 0.5 kcal/mol lower in
energy than free B(C6F5)3, and coordination of the borane to
the 4-fluorobenzoic acid stabilized by the amine (9) which
was calculated to be 4.6 kcal/mol lower in energy than free
B(C6F5)3 (Figure 2). This off-cycle intermediate significantly
raises the total overall energy barrier for the reaction, which
is in accordance with our reaction conditions.
the first case, this protonates the ester 2, yielding carbenium
Table 2. Calculation of the energy barrier to generate the carbenium ion
intermediate from 2 at different levels of theory.
intermediate I2. The activation barrier for the overall
reaction was found to be much lower in this case (11.3 to
16.1 kcal/mol in this case when calculated at a range of levels
of theory (Table 2). However, experimental results (Table 1,
entry 6) showed no conversion using p-fluorobenzoic acid as
a catalyst.
Finally, we turned our attention to the Lewis acid
catalyzed pathway in which boron acts as a Lewis acid
catalyst to activate the ester (Scheme 3c). DFT studies
showed that the formation of a 1:1 ester:borane adduct was
favorable over a 1:2 adduct.22 Calculations into the reaction
indicated that this pathway was also favorable under the
reaction conditions with an activation barrier of 18.2
kcal/mol relative to the starting materials (Figure 2). It was
Lewis
acid
Brønsted
acid
Level of Theory
catalyzed catalyzed
CPCM/ωB97XD/def2-TZVP//CPCM/B3LYP/6-
31G(d)
CPCM/ M06-2X/def2-TZVP//CPCM/B3LYP/6-
31G(d)
SMD/ωB97XD/def2-TZVP//CPCM/B3LYP/6-
31G(d)
SMD/M06-2X/def2-TZVP//CPCM/B3LYP/6-
31G(d)
10.6
13.5
11.1
14.1
10.8
12.3
14.8
13.5
16.1
11.3
SMD/ M06-2X-D3/def2-
TZVP//CPCM/B3LYP/6-31G(d)
found that coordination of the borane to the ester 2 was the
initial step of the reaction to give the adduct I1 via a low
energy transition state (TS1) of 7.5 kcal/mol. I1 was found to
have an elongated C–O bond length of 1.510 Å, which results
in bond cleavage and the generation of an electrophilic
carbenium ion in salt I2 occurring with an activation barrier
Conclusions
In conclusion,
a
simple facile metal-free reaction
methodology has been demonstrated for the construction of
C–N bond through N-alkylation using catalytic amounts of
B(C6F5)3. A wide range of substrates was tested including
secondary amines, carbazoles and indoles to give good to
excellent yields of the N-alkylated products. Interestingly,
when 1H-indole and 1H-pyrrole were used for the reaction,
exclusive C–C cross-coupled products were obtained. DFT
studies have shown that the role of the catalyst is to act as a
Lewis acid to generate an electrophilic carbenium ion which
is then attacked by the amine nucleophile. Overall, this work
represents a mild metal-free approach to construct the C–N
bond via N-alkylation reaction and adds to the range of
reactions the special Lewis acid B(C6F5)3 can catalyze.
of 13.6 kcal/mol through TS2
reacts with the amine nucleophile
.
I2 exists as a close ion pair and
via TS3 (activation
1
barrier 7.6 kcal/mol) to give I3 then I4. Finally, deprotonation
through TS4 with a low activation barrier of 7.0 kcal/mol
releases the by-product 4-fluorobenzoic acid to generate the
N-alkylated product and to regenerate the B(C6F5)3 catalyst.
In the 1:1 stoichiometric reaction of the ester with 2a with
B(C6F5)3, p-fluorobenzoic acid was isolated supporting this
pathway.
Since the overall activation energy for formation of
carbenium species for latter two pathways (b and c) were
quite similar, we compared the energy barrier for this step
at various levels of theory (Table 2). In all cases, the energy
barrier was slightly lower by 0.5 to 2.4 kcal/mol for the Lewis
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Supplementary Information includes detailed experimental
Conflicts of interest
There are no conflicts to declare.
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procedures, NMR spectra, DFT daDtaO,I: 1a0n.1d039X/D-r0aCyY01d3a3t9aK.
Crystallographic data for 4c and 5a have been deposited in the
Cambridge Crystallographic Data Centre (CCDC) under
accession numbers CCDC: 1996990 and 1996991. These data
can be obtained free of charge from the CCDC at
Acknowledgements
A.D. and R.L.M. are grateful to the EPSRC for funding
(EP/R026912/1). We acknowledge Dr. Benson Kariuki
(Cardiff University) for XRD measurements and for solving
and refining data.
http://www.ccdc.cam.ac.uk/data_request/cif
.
Information
about the data that underpins the results presented in this
article, including how to access them, can be found in the
Cardiff University data catalogue at http://doi.org/xxx
Data availability
Notes and references
1
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•
•
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B(C6F5)3 is demonstrated to be an active catalyst for N-alkylation reactions of amine subsDtrOaI:t1e0s.10w3i9t/hD0CY01339K
aryl esters.

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DOI: 10.1039/D0CY01339K
275x192mm (96 x 96 DPI)