Direct N-Alkylation/Fluoroalkylation of Amines Using Carboxylic Acids via Transition-Metal-Free Catalysis

Article abstract of DOI:10.1002/adsc.202000679

A scalable protocol of direct N-mono/di-alkyl/fluoroalkylation of primary/secondary amines has been constructed with various carboxylic acids as coupling agents under the catalysis of a simple air-tolerant inorganic salt, K₃PO₄. Advantageous features include 100 examples, 10 drugs and drug-like amines, fluorinated complex tertiary amines, gram-scale synthesis and isotope-labelling amine, thus demonstrating the potential applicability in industry of this methodology. The involvement of relatively less reactive silicon-hydride compared with the traditional reactive metal-hydride or boron-hydride species required to reduce the amide intermediates presumably contributes to the remarkable functional group compatibility. (Figure presented.).

Full text of DOI:10.1002/adsc.202000679

Title: Direct N-Alkylation/Fluoroalkylation of Amines Using Carboxylic
Acids via Transition-Metal-Free Catalysis
Authors: Bo-Lin Lin, Chunlei Lu, Zetian Qiu, Maojie Xuan, Yan Huang,
Yongjia Lou, Yiling Zhu, and Hao Shen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000679
Link to VoR: https://doi.org/10.1002/adsc.202000679

10.1002/adsc.202000679
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202000679
Direct N-Alkylation/Fluoroalkylation of Amines Using
Carboxylic Acids via Transition-Metal-Free Catalysis
Chunlei Lu, ‡abc Zetian Qiu, ‡a Maojie Xuan,d Yan Huang,d Yongjia Lou,a Yiling Zhu,a
Hao Shena and Bo-Lin Lin abc*
a
School of Physical Science and Technology (SPST), ShanghaiTech University, Shanghai 201210, P. R. of China
E-mail: linbl@shanghaitech.edu.cn
b
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, P. R. of
c
d
China
‡
These two authors contributed equally.
Received: ((will be filled in by the editorial staff))
Abstract:
A scalable protocol of direct N-mono/di-
alkyl/fluoroalkylation of primary/secondary amines has been
constructed with various carboxylic acids as coupling agents
under the catalysis of a simple air-tolerant inorganic salt,
K3PO4. Advantageous features include 100 examples, 10
drugs and drug-like amines, fluorinated complex tertiary
amines, gram-scale synthesis and isotope-labelling amine,
thus demonstrating the potential applicability in industry of
this methodology. The involvement of relatively less reactive
silicon-hydride compared with the traditional reactive metal-
hydride or boron-hydride species required to reduce the amide
intermediates presumably contributes to the remarkable
functional group compatibility.
Keywords: N-mono/di-alkylation/fluoroalkylation;
Amines; Lewis base; C–N cross-coupling; Carboxylic acids
stability, handling convenience, structural diversity
and ubiquity in nature2.
Introduction
Cross-coupling reactions catalyzed by transition
metals have fundamentally changed modern organic
syntheses. The emergence of a new type of substrates
containing a reactive C–X or C–M bond (X: Cl, Br, I,
etc.; M: B, Si, Sn, Zn etc.) is the hallmark of classical
cross-coupling reactions such as Heck reactions,
Suzuki reactions, and Stille reactions. These different
types of substrates often display complementary
functional group tolerance, enabling widespread
applications in preparing valuable products including
pharmaceuticals, materials and agrochemicals1.
However, classical cross-coupling reactions suffer
from issues such as the air/moisture-sensitivity of C-
M bonds, the toxicity of transition metal catalysts and
organic halides, and the limited substrate commercial
availability2. To partially address these issues,
carboxylic acids as a coupling reagent have attracted
surging research attention recently due to advantages
such as low cost, high availability, low toxicity, great
1
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10.1002/adsc.202000679
Advanced Synthesis & Catalysis
Scheme 1. Classical N-alkylation of amines and the
present catalytic method.
We recently found that alkali metal carbonates,
especially cesium carbonate and potassium carbonate,
can act as an efficient catalyst for direct N-methylation
of amines, a special type of N-alkylation reaction, with
CO2 and hydrosilanes8-9. We wondered whether such
kind of simple inorganic bases can also be applied in
direct N-alkylation of amines with carboxylic acids.
To test this hypothesis, we first chose N-methylaniline,
trifluoroacetic acid and PhSiH3 as the model substrates.
To our delight, almost all studied simple inorganic
salts led to the desired reactivity (Table S1). The best
result was obtained with K3PO4. Subsequent studies
indicate that the reaction was sensitive to hydrosilanes
(Table S2). Only a moderate yield was observed for
PMHS, while all other silanes, including
triethoxysilane, triphenylsilane, diphenylsilane, and
TMDS, only afforded a zero to low yield. Upon
screening and optimization of reaction conditions, a
93% yield was achieved upon performing the reaction
in THF at 80 oC for 12 h in the presence of a 10 mol%
loading of K3PO4, a 20 mol% loading of 18-crown-6
and 10 mg molecular sieve (Tables S3, S4).
Direct N-alkylation of amines using carboxylic
acids (DNACA)3 functions as a new cross-coupling
reaction that may offer great opportunities to afford
various alkyl amines—a ubiquitous moiety in
pharmaceuticals, materials, and agrochemicals4.
Considering the presence of sp3 C–N bonds in over
50% of top-selling drugs5, wide-scope sp3 C–N
coupling reactions is of particular importance. In
medicinal chemistry, however, direct N-alkylation of
amines often employ toxic and relative air-sensitive6
alkyl halides or aldehydes to install sp3 C–N bonds7
(Scheme 1a). Undesired overalkylations of amines
often tend to occur. Consequently, development of
new synthetic tools for selective construction of sp3 C–
N bonds still remains at the center stage of current
organic research. Several elegant catalytic systems
3c
using an air-sensitive Lewis acid (B(C6F5)3 ) and
transition metal complexes (Fe3k, Co3j, Ni3m, Ru3d, 3f
,
Pt3b, Rh3g, and Ir3e) with silane or H2 have been
developed for DNACA recently, together with one
catalyst free system employing ammonia borane as the
reductant3l. However, the mechanisms of all these
systems involve the reactive metal-hydride or boron-
hydride species, leading to relatively limited
functional group tolerance (Scheme 1b). We recently
showed that mild nucleophilic activation of relatively
less reactive silicon-hydride provides an alternative
way to reduce CO2, in which the formation of metal-
hydride or boron-hydride species can be avoided8.
This corresponds well with Denton’s elegant catalyst-
free system in spite of its limited substrate scope,
because it also doesn’t proceed through the amide
intermediates under mild reducing atmosphere3i.
Therefore, we reasoned that suitable reducing capacity
may enable the application of DNACA to a wide scope
of amines. In particular, DNACA with fluoro-
carboxylic acids—a category of inexpensive, bench
stable and widely commercially available reagents—
appears to be a highly attractive method to synthesize
N-fluoroalkylated amines that are highly desirable in
pharmaceutical industry.
Figure 1. Scope of N-fluoroalkylation of secondary
amines. (A) With trifluoroacetic acid as the N-
fluoroalkylation agent. (B) With 4-(trifluoromethyl)benzoic
acid as the N-fluoroalkylation agent. Reaction conditions:
amine (0.25 or 0.5 mmol), PhSiH3 (4 equiv), acid (4.6 equiv),
K3PO4 (0.1 equiv), 18-crown-6 (0.2 equiv), 4Å MS (10 or
20 mg), 80 oC, 12 h. [b] 4 h. [c] 0.125 mmol amine.
Herein, we report a transition metal-free, air-
tolerant and easy-to-handle catalytic system for direct
N-alkylation of various primary and secondary amines
with a wide scope of carboxylic acids (>100 examples,
Scheme 1b). Applications in a gram-scale reaction as
well as preparations of 4 drug molecules, 7 N-
fluorolalkylated drug molecules, a 13C-labelled amine
With the optimized conditions in hand, we first
examined its applicability in fluoroalkylation of
secondary amines using aromatic/aliphatic fluoro-
carboxylic acids with the aim to introduce fluorine
atoms considering its beneficial effects for drugs or
drug candidates10 and the diversity of commercially
available fluorine-containing carboxylic acids. As
shown in Fig. 1, wide scopes of secondary amines
were successfully fluoroalkylated for both
13
from a readily available C-labelled carboxylic acid,
an enantiopure vicinal diamine from natural amino
acid, and fluorinated complex tertiary amines from
simple primary amines were also demonstrated via
simple inorganic base catalysis. Mechanistic studies
suggest that the reactions occur through the acetal
mechanism, consistent with the proposed relatively
mild reductive strategy and the observed wide
substrate scope.
trifluoroacetic
acid
(Fig.
1A)
and
4-
(trifluoromethyl)benzoic acid (Fig. 1B). Several
prominent features are noted: i) a remarkably wide
scope of functional groups, including various
Results and Discussion
1
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10.1002/adsc.202000679
Advanced Synthesis & Catalysis
unsaturated ones (10-12, 14-15, 27-29, 35-36, 39:
ketone, ester, amide, cyano, and olefinyl groups), are
well tolerated. Notably, it is the first time that ketone
carbonyl can be compatible in this type of reaction (10,
27); ii) as to remote substitution effect onto anilinic
derivatives, both electron-donating and electron-
withdrawing groups are tolerated, but lower yields
were observed for anilinic derivatives with electron-
withdrawing groups (4-11, 23-29); iii) the position of
chloro substituent at the anilinic phenyl ring, ortho-,
meta- or para-, doesn’t appear to have a significant
impact onto the reaction yield (1-2, 5, 24, 31); iv)
moderate to excellent yields were successfully
achieved for secondary amines with relatively high
steric hindrance (13, 14, 34, 37); v) good to excellent
yields were obtained non-anilinic or aliphatic amines
(16-22, 33, 37-39); vi) moderate to good yields were
successfully obtained for cyclic amines (16-18, 22,
30); vii) it’s worth mentioning that the reaction is
compatible with a classical nucleophilic site—
hydroxyl group (18); and viii) a gram-scale reaction
afford good to excellent yields (43, 48, 50, 53, 55-58),
clearly proving the great potentials in synthesizing
fluorine-containing amines; iv) alkylation of N-
methylaniline by 13C-labelled benzoic acid was tested,
leading to a 70% yield of the desired 13C-labelled
product (45). Carbon-isotope-labelled carboxylic
acids can be readily prepared from isotopologues of
CO2 (11CO2, 13CO2, and 14CO2), the primary source of
carbon-isotope-labelled compounds14. As such, the
present protocol might also be useful to make carbon-
isotope-labelled amines that have found important
applications in drug absorption, distribution,
metabolism and excretion (ADME)15; and v) a random
pick of three acids to react with N-ethylaniline also
provided excellent yields (57-59), indicating that the
scope of amines is not limited to N-methylaniline.
was
attempted
for
N-(1-Methylethyl)-
benzenemethanamine (37), leading to an isolated yield
almost identical to its small-scale counterpart.
The success in N-fluoroalkylation of amines with
trifluoroacetic acid indicates that the present protocol
might be a useful tool to introduce fluorine atoms to
the β-position of the N atom of complex secondary
amines, which has shown beneficial effects for some
drugs or drug candidates 10. To date, besides Denton’s
non-catalytic trifluoroethylation of secondary aliphatic
3i
amines
, only limited examples have been
demonstrated previously for syntheses of N-
Figure 2. Substrate scope of carboxylic acids. (A)
With simple various carboxylic acids as the N-
alkyl/fluoroalkylation agent. (B) With boc-protected amino
acids as the N-alkylation agent. Reaction conditions: A,
amine (0.25 mmol). B, amine(0.125mmol). PhSiH3 (4
equiv), acid (4.6 equiv), K3PO4 (0.1 equiv), 18-crown-6 (0.2
equiv), 4Å MS (10 mg), 80 oC, 12 h.
trifluoroethylated aniline derivatives using relatively
unstable trifluoroethylation reagents, such as
11
trifluoroacetaldehyde
and
2,2,2-
trifluorodiazoethane12, or Pd-catalyzed coupling of
aryl halides and trifluroethylamine13. The present
protocol provides an air-tolerant alternative approach
under transition metal-free conditions. Besides, given
the diversity of commercially available fluoro-
containing carboxylic acids, we envisioned that the
present methodology should be a convenient tool to
introduce various different kinds of fluoroalkyl groups
into amines.
After successfully establishing the general
applicability of the present protocol in secondary
amines, we next investigated the scope of carboxylic
acids. As shown in Fig. 2a, in addition to a remarkable
compatibility of functional groups (42-44, 49-53:
methoxyl, fluoro, ketone and trifluoro methyl group,
nitro, cyano and olefinyl group), several other notable
features can be observed: i) aromatic carboxylic acids
with an either electron-donating or electron-
withdrawing group are well tolerated, but N-
methylaniline with electron-withdrawing groups
exhibits higher yields than those with electron-
donating groups (40-44, 49-52); ii). The reaction was
also successfully extended to pharmaceutically
important heterocyclic carboxylic acids7, such as 2-
furoic acid and 2-thiophenecarboxylic acid (46, 47,
59); iii) diverse fluorine-containing synthons also
With the established protocol, vicinal diamines are
also easily accessible by using α-amino acids as the
alkylation agent (Fig. 2B). The boc-protecting group is
well tolerated, which allows chemoselective alkylation
of the unprotected amines (60-62). Notably, the
enantiopurity of alanine is fully retained (60),
demonstrating the great potential to use natural amino
acids to prepare various chiral vicinal diamines via this
methodology.
We next examined the applicability of the present
protocol to primary amines. Classical alkylation
reactions often suffer from overalkylation issues due
to the lack of chemoselectivity among primary,
secondary, and even tertiary amines. The present
protocol,
however,
displays
excellent
chemoselectivity N-monoalkylation for a broad range
of primary amines (Fig. 3a, 63-84) and carboxylic
acids compared with the classical alkylation reactions.
By comparing the yields for reactions between aniline
and various carboxylic acids (63,72-77), weaker acids
seem to be more favourable than stronger acids in the
N-monoalkylation of primary amines.
1
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10.1002/adsc.202000679
Advanced Synthesis & Catalysis
its utilities in direct N-fluoroalkylation of drug-like
amines
with
trifluoroacetic
acid
or
4-
(Trifluoromethyl)benzoic acid for 6 commercial drugs
(Fig. 4a, 91-97), including Paroxetine, Nortriptyline,
Tomoxetine, Fluoxetine, Nornicotine, and Sertraline.
The good to excellent yields indicate the great
potentials in modifications of drug-like amines. To
further demonstrate its potential applicability in
medicinal chemistry, we applied the present
methodology to the syntheses of 4 commercial drug
molecules, including the anti-hyperparathyroidism
drug Cinacalcet17, the antiparkinsonian drug Piribedil,
and the antifungal drugs Naftifine and Butenafine (Fig.
4b, 98-100). All of them can be conveniently
synthesized with moderate to excellent yields.
Four possible pathways with two branch points can
be envisioned for the reaction mechanism (Scheme 2).
Hydrosilane was activated by nucleophilic activator
Figure 3. Substrate scope of N-mono/di-alkylation of
primary amines with various carboxylic acids. (A) N-mono-
alkyl/fluoroalkylation of primary amines. (B) N-di-
alkyl/fluoroalkylation of primary amines. Reaction
conditions: A, acid (4.6 equiv), 12h; B, acid 1 (2.3 equiv),
acid 2 (2.3 equiv), 24h. Amine (0.25 mmol), PhSiH3 (8
equiv), K3PO4 (0.1 equiv), 18-crown-6 (0.2 equiv), 4Å MS
(10 mg), THF (1.6 mL), 80 oC.
-
-
(K2PO4 or RCO2 ) via a high coordinated intermediate
A. After formation of silyl ester from dehydrogenative
coupling of carboxylic acid and silane, the first branch
point arises. The ensuing silyl ester may directly react
with an amine to form an amide, which can be further
reduced to yield the final N-alkylation product
(Pathway 1). Alternatively, a further reduction of the
silyl ester may occur to afford a silyl acetal/hemiacetal,
leading to the second branch point with three
mechanistic ramifications: i) instantaneous capturing
of the silyl acetal by an amine forms an iminium
intermediate, which can be further reduced to the
product (Pathway 2); ii) the silyl acetal can undergo an
equilibrium with the corresponding aldehyde, which
may result in the N-alkylation product through a
classical reductive amination process (Pathway 3); and
iii) a subsequent reduction of the acetal occurs first to
generate the alcohol or the corresponding silyl ether
prior to the final formation of the product with amine
(Pathway 4).
Synthesis of complex tertiary amines from readily
available simple amines is highly desired16. Inspired
by the apparent reactivity pattern for primary amines
and its wide applicability for secondary amines, we
successfully installed two different alkyl groups onto
simple primary amines in a one-pot, two-step fashion.
Given the tendency that primary amines favor
relatively weak acids, sequential additions of a weaker
acid and a stronger acid successfully led to complex
fluorinated tertiary amines with three different
substituents (Fig. 3b, 85-90).
Scheme 2. Possible pathways for the N-alkylation
reactions. (The square bracket of [Si] represents multiple Si
complexes with potentially different coordination numbers
or ligands of Si.)
Figure 4.
Substrate scope of N-alkylation of drug-
We then interrogated the potential reaction
mechanism for this simple inorganic base catalysis.
The formation of silyl ester was confirmed through the
real-time monitoring by in situ 1H NMR (Fig. S1-S3).
The inertness of the ensuing amide under the present
catalytic conditions (Scheme S2) directly rules out
Pathway 1, which distinguishes it from the previous
catalytic DNACA3b-e. In the absence of amine, both
aldehyde and alcohol can be detected from reduction
like amines. (A) N-alkylation of drugs. (B) Synthesis of
drugs. Reaction conditions: acid (4.6 equiv), amine (0.25
mmol), PhSiH3 (8 equiv), K3PO4 (0.1 equiv), 18-crown-6
(0.2 equiv), 4Å MS (10 mg), THF (1.6 mL), 80 C, 4h. [b]
8h. [c] 12h. [d] 36h.
o
Encouraged by the wide applicability of this new
methodology among simple amines, we next evaluated
1
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10.1002/adsc.202000679
Advanced Synthesis & Catalysis
Schlenk tube. Amine (0.25 mmol, 1 equiv), acetic acid or
isobutyric acid (2.3 equiv) and PhSiH3 (8 equiv) were added
into the tube in the air. The mixture was stirred at 80 oC for
12 h. Then, fluoro-containing acid (2.3 equiv) was added
of the starting carboxylic acids (Scheme S1). However,
neither of them can react with the starting amine to the
desired product under the present catalytic conditions
(Scheme S2), disfavoring Pathway 3 and Pathway 4. It
should be pointed out that although the aldehyde
mechanism leads to great performance in the previous
catalytic systems3j, 3m, this pathway seems to be
inaccessible in the simple inorganic base catalysis,
consistent with our original design of the catalytic
strategy. As such, Pathway 2 appears to be the
preferred mechanism under current conditions. This
notion is further supported by the reduction of N-
benzylideneaniline to the N-phenylbenzylamine by the
PhSiH3 via K3PO4 (Scheme S2), which also seems to
suggest that the conversion of amine and aldehyde to
the corresponding imine is not favored under the
present conditions.
o
and the reaction mixture was allowed to be stirred at 80 C
for 12 h. The reaction mixture was concentrated, and
purified by silica gel or Isolera Flash Chromatography to
provide the desired product.
Acknowledgements
We thank the National Natural Science Foundation of China
[NSFC U1532135] for the financial support.
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Conclusion
In summary, we have developed an efficient and
versatile method for the synthesis of alkyl/fluoroalkyl
amines via transition metal-free catalysis. 100 amines
with diverse functional groups can be readily prepared.
The successful synthesis of 11 drug-related molecules
highlights the potential application of this catalytic
system in making complex molecules.
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Experimental Section
Remarks. Solvents were treated with solvent purification
systems before use. The deuterated solvents were purchased
from J&K Scientific Ltd. Purification of products was
accomplished by flash chromatography using silica gel or
Isolera Flash Chromatography. 1H, 13C, and 19F NMR
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performed on ThermoFisher Q-Exactive Focus.
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carried out on Agilent 7890B Infinity system. Trace metal
analysis were carried out on ICP-MS (Thermo Fisher, i CAP
Q).
General procedures A for alkylation of secondary
amines. In a glovebox, K3PO4 (0.1 equiv), 18-crown-6 (0.2
equiv), 4Å molecular sieve (powder) (10 or 20 mg) and THF
(1.6 or 2.5 or 3.2 mL) were added into a Schlenk tube.
Amine (0.25 or 0.5 mmol, 1 equiv), acid (4.6 equiv) and
PhSiH3 (4 equiv) were added into the tube in the air. The
mixture was stirred at 80 oC for 4-12 h. The reaction mixture
was concentrated and purified by silica gel or Isolera Flash
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10.1002/adsc.202000679
Advanced Synthesis & Catalysis
UPDATE
Direct N-Alkylation/Fluoroalkylation of Amines
Using Carboxylic Acid via Transition-Metal-Free
Catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Chunlei Lu, ‡abc Zetian Qiu, ‡a Maojie Xuan,d Yan
Huang,d Yongjia Lou,a Yiling Zhu,a Hao Shena and
Bo-Lin Lin abc
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