Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids

Article abstract of DOI:10.1002/anie.201503879

A boron-based catalyst was found to catalyze the straightforward alkylation of amines with readily available carboxylic acids in the presence of silane as the reducing agent. Various types of primary and secondary amines can be smoothly alkylated with good selectivity and good functional-group compatibility. This metal-free amine alkylation was successfully applied to the synthesis of three commercial medicinal compounds, Butenafine, Cinacalcet. and Piribedil, in a one-pot manner without using any metal catalysts.

Full text of DOI:10.1002/anie.201503879

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International Edition: DOI: 10.1002/anie.201503879
German Edition: DOI: 10.1002/ange.201503879
Synthetic Methods
Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids**
Ming-Chen Fu, Rui Shang,* Wan-Min Cheng, and Yao Fu*
Abstract: A boron-based catalyst was found to catalyze the
straightforward alkylation of amines with readily available
carboxylic acids in the presence of silane as the reducing agent.
Various types of primary and secondary amines can be
smoothly alkylated with good selectivity and good functional-
group compatibility. This metal-free amine alkylation was
successfully applied to the synthesis of three commercial
medicinal compounds, Butenafine, Cinacalcet. and Piribedil,
in a one-pot manner without using any metal catalysts.
group elements, we proposed that a boron-based catalyst,
which has utility in amide condensations[6] and amide
reductions with a silane,[7a] might also serve as a suitable
catalyst for this process. Herein we show that a boron-based
catalyst, B(C6F5)3, which can form a frustrated Lewis pair
(FLP),[8,9] can catalyze the straightforward N-alkylation of
amines using carboxylic acids in the presence of a silane
reducing agent with good selectivity and good functional-
group compatibility (Scheme 1). The boron catalyst enables
efficient reductive carbon–nitrogen bond formation in pref-
erence to the undesired reduction of the carboxylic acid. The
required loading of the boron catalyst is only 1 mol% and can
be used for a wide scope of substrates, thus generating
products in good yield. A turnover number up to 700 was
achieved. The work presented herein provides a new metal-
free method of synthesizing alkylated amines using carboxylic
acids, and it also demonstrates a new example of reductive
carbon–nitrogen bond formation through FLP catalysis.
Because formic acid is an ideal C1 source derived from
biomass,[10] and methylated amine structures appear widely in
pharmaceuticals,[11] our research started with the methylation
of N-methylaniline with formic acid,[10a,12] as demonstrated in
Table 1. The optimal reaction conditions, discovered after
systematic optimization, are listed in entry 1 of Table 1.
Phenylsilane (0.8 mmol) was added by a gas-tight syringe to
A
lkylation of amines is an important process, in both
laboratory synthesis and the chemical industry.[1] Alkylated
amine structures appear widely in pharmaceuticals, agro-
chemicals, and materials.[2] Traditional methods of alkylating
an amine include noncatalytic reactions using hazardous alkyl
halides for substitutions,[3] or using air-sensitive aldehydes for
reductive aminations.[4] Compared with traditional methods,
a general catalytic method for the alkylation of amines
utilizing carboxylic acid is more appealing because of the step
economy and easy availability of the carboxylic acids.
Recently, direct catalytic alkylation of amines using carbox-
ylic acids was achieved by Beller et al. and they utilized
a platinum/diphosphine-based catalyst (Scheme 1).[5] With
our interest in sustainable catalysis using abundant main
a
mixture of N-methylaniline (0.2 mmol), formic acid
(0.46 mmol), and tris(perfluorophenyl)borane (1.0 mol%,
0.002 mmol) in dibutyl ether. After heating the mixture at
1008C for 8 hours, N,N-dimethylaniline (2a) was obtained
quantitatively. No amide byproduct (3a) was detected.
Parameters which control this reaction are also given in
Table 1. A control experiment showed that B(C6F5)3 is
essential for this reaction; without the catalyst, only the
amide byproduct can be detected (entry 2). Other boron
catalysts, such as trifluoroborane (entry 3) and a boronic ester
(entry 7), are not effective catalysts. Boronic acids, which
were previously reported to be effective for amide condensa-
tions[6] and amide reductions,[7a] are totally ineffective for this
one-pot amine alkylation reaction (entries 5 and 6). Other
boron catalysts and metal Lewis acid catalysts (see the
Supporting Information) failed in serving as an efficient
catalyst, thus suggesting that the tris(perfluorophenyl)borane
does not only act simply as a Lewis acid catalyst. The unique
catalytic activity of tris(perfluorophenyl)borane may be
attributed to its ability to form an FLP with carbonyl groups
Scheme 1. Catalytic N-alkylation of amines using carboxylic acids.
[*] M.-C. Fu, Dr. R. Shang, W.-M. Cheng, Prof. Y. Fu
iChEM, CAS Key Laboratory of Urban Pollutant Conversion, Anhui
Province Key Laboratory of Biomass Clean Energy, Department of
Chemistry, University of Science and Technology of China
Hefei 230026 (China)
to activate the silane[13] and thus induce reductive C N bond
À
E-mail: faint123@mail.ustc.edu.cn
formation. Although Et3SiH failed to serve as a reducing
agent for this reaction (entry 8), PMHS (polymethylhydro-
siloxane), Et2SiH2, and Ph2SiH2 all served as reducing agents
(entries 9–11). The lower reactivity of the tertiary silane,
compared with that of the secondary silane, may be ascribed
to the steric effect. It should be noted that PMHS is a cheap,
fuyao@ustc.edu.cn
[**] This work was supported by the 973 Program (2012CB215306),
NSFC (21325208, 21172209, 21361140372), IPDFHCPST
(2014FXCX006), CAS (KJCX2-EW-J02), FRFCU, and PCSIRT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503879.
9042
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Table 1: Catalytic N-methylation of N-methylaniline using formic acid.[a]
Table 2: N-methylation of various amines with formic acid.[a]
Yield [%][b]
2a
Entry
Catalyst
Silane
Solvent
3a
1
2
B(C6F5)3
none
BF3 OEt2
Et3B
A
B
PhSiH3
PMHS
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
Et3SiH
PMHS
Et2SiH2
Ph2SiH2
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
nBu2O
1,4-dioxane
toluene
mesitylene
DMF
acetonitrile
nBu2O
99
0
5
49
1
1
–
45
3
2
5
10
5
61
–
–
–
–
–
2
51
61
4
3[c]
4[c,d]
5[c]
6[c]
7[c]
8
C
<1
6
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
9
98
97
92
96
95
90
5
2
92
72
10
11
12
13
14
15
16
17[e]
18[f]
nBu2O
26
[a] Reaction conditions: N-methylaniline (0.2 mmol), silane (4.0 equiv),
catalyst (1.0 mol%), HCO2H (2.3 equiv), solvent (1.0 mL), 1008C, 8 h.
[b] Determined by GC analysis of the reaction mixture after quenching
with aqueous NaOH solution. n-Dodecane was used as an internal
standard. [c] Catalyst (5.0 mol%). [d] Et3B in a THF solution
(1.0 molLÀ1). [e] B(C6F5)3 (0.5 mol%). [f] B(C6F5)3 (0.1 mol%).
PMHS=polymethylhydrosiloxane.
[a] Reaction conditions for secondary amines: substrate (0.2 mmol),
PMHS (4.0 equiv), B(C6F5)3 (0.5 mol%), HCO2H (2.3 equiv), nBu2O
(1.0 mL), 1008C, 8–10 h. For primary amines: substrate (0.2 mmol),
PMHS (8.0 equiv), B(C6F5)3 (1.0 mol%), HCO2H (4.0 equiv), nBu2O
(2.0 mL), 1008C, 8–15 h. [b] Yield of isolated product. [c] Determined by
GC analysis using n-dodecane as an internal standard instead of
isolation. [d] PMHS (5.0 equiv). [e] PMHS (3.5 equiv), 8 h. [f] PhSiH3
(8.0 equiv). [g] 1208C, 18 h. [h] PMHS (3.0 equiv), HCO2H (1.3 equiv),
1,4-dioxane (1.0 mL), 1108C, 3 h; the yield of the dimethylation product
is given within parentheses.
stable, and environmentally friendly hydrosilane, which is
more suitable to serve as a reducing agent for large-scale
production.[14] A study of the solvent effect revealed that
ethers and arenes are suitable solvents (entries 12–14), but
polar solvents such as DMF (entry 15) and acetonitrile
(entry 16) are unsuitable. It is notable that the catalyst
loading can be lowered to 0.5 mol% and still lead to 92% of
the desired product. Further lowering the loading to
0.1 mol% gave the product in 72% yield.
With the optimal reaction conditions in hand, we inves-
tigated the scope of this reaction using formic acid and various
amine coupling partners (Table 2). Various N-methylanilines
can be successfully methylated in excellent yield (entries 1–4
and 10). The electronic effect on the phenyl ring has no
significant effect on the reaction outcome (entries 4 and 10).
N-ethyl and N-benzylaniline can also be successfully methy-
lated with formic acid in excellent yield (entries 5 and 8).
Indoline also gives the N-methylated product in high yield
(entry 6). Besides N-alkylated aniline, methylation of diphe-
nylamine also took place smoothly (entry 7). Indole gives 1-
methylindoline as the major product, in which the double
bond is hydrogenated during the reaction. This reaction also
has good functional-group compatibility; an aryl chloride
(entry 2), aryl bromide (entry 3), ether (entry 4), and thio-
ether (entry 17) are all well tolerated. It is surprising to find
that even a nitro group (entry 10) and cyano group (entry 12)
are well tolerated without any undesired reduction. A
terminal alkene structure, which is sensitive to transition-
metal catalysis, also remained intact (entry 11). Although
there are reports that the combination of silane and a borane
catalyst can directly reduce alcohols to alkanes,[15a,b] in our
reaction, an alcohol is tolerated (entry 13). The ketone
functionality cannot be tolerated, and instead a high yield of
the deoxygenated product was obtained (entry 14). Esters can
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Table 3: N-Alkylation with various carboxylic acids.[a]
be partially tolerated by reducing the amount the silane used
(entry 15). The reaction is not limited to secondary amines as
it also works well for primary amines. The reaction of aniline
can selectively give the dimethylated products (entries 16–
18). Steric bulk on the ortho position of the aniline is well
tolerated (entry 16). Basic-nitrogen-containing heteroaro-
matic amines are important structural motifs in pharmaceut-
icals, and their alkylation using alkyl halides always causes
undesired side reactions.[16] Our method can also be applied to
the alkylation of nitrogen-containing heteroaromatic amines
as demonstrated the selective demethylation of by pyridin-2-
amine and benzo[d]thiazol-2-amine in excellent yields
(entries 19 and 20). Not only aromatic amines but also
aliphatic amines are suitable substrates, for piperidine and
morpholine are methylated in high yield (entries 21 and 22).
An interesting domino reductive alkylation of an imine was
observed wherein the imine can be reduced in situ and
alkylated in one pot (entry 23 ). For a primary amine, the
degree of methylation can be controlled by tuning the
stoichiometry of the reagent (entry 24).
After evaluating the scope with respect to amine coupling
partners, we also studied the scope of carboxylic acids to
explore the generality of this method. Table 3 summarizes the
results to demonstrate the scope with respect to the carboxylic
acid coupling partner. For acetic acid, both monoethylation
and diethylation can be selectively achieved by adjusting the
stoichiometry of the reagent (see the Supporting Information
for details). It was found that when carboxylic acids with
longer chains were used, monoalkylation products were the
major products. For alkylation of aniline with 2-phenylacetic
acid or 3-phenylpropanoic acid, mono-N-alkylation products
were obtained in good yield, and no dialkylation was
observed. It is interesting that the nitro group on the
carboxylic acid is also compatible. Aryl bromides remain
intact in this metal-free process and make additional func-
tionalization by cross-coupling reactions possible. Hexanoic
acid gives the mono-N-hexyl-substituted aniline in good yield
(entry 7). Importantly, using 2,2,2-trifluoroacetic acid and
3,3,3-trifluoropropanoic acid gives the trifluoromethyl-con-
taining aniline product in moderate yields (entries 8 and 9).
These trifluoromethyl-containing anilines are useful building
blocks in the pharmaceutical industry. When biomass-derived
lactic acid was used, the N-propyl-substituted product was
obtained, thus demonstrating that a hydrodeoxygenation
process also took place to remove the a-OH group, and
making lactic acid a suitable C3 source for propylation
(entry 10). Using acrylic acid also gives the N-propyl-sub-
stituted product (entry 11). Tertiary carboxylic acids, such as
cyclohexanecarboxylic acid and cyclohex-3-ene-1-carboxylic
acid, also gave the monoalkylated products in good yields
without detection of any dialkylation. It should be noted for
cyclohex-3-ene-1-carboxylic acid that the cyclohexene moiety
remains intact. Sulfur-containing carboxylic acids are ame-
nable substrates (entries 14 and 15). We also tried to apply
biomass-derived levulinic acid to this transformation, and it
was found that phenylpyrrolidinone and phenylpyrrolidine
can be selectively obtained in high yields by tuning the
stoichiometry of the silane agent. When 5-bromopentanoic
[a] Reaction conditions: aniline (0.2 mmol), B(C6F5)3 (1.0 mol%), PMHS
(5.0 equiv), acids (1.7 equiv), toluene (1.5 mL), 1008C, 13 h. [b] Yield of
isolated product. [c] Determined by GC analysis using n-dodecane as an
internal standard instead of isolation. [d] CH3CO2H (5.0 equiv), PMHS
(7.0 equiv). [e] 2-Hydroxypropanoic acid (2.0 equiv), PhSiH3 (4.0 equiv),
20 h. [f] PMHS (6.0 equiv). [g] PMHS (2.5 equiv).
substitution took place to deliver 1-phenylpiperidine
(entry 18). It should be noted that the undesired reduction
of the carboxylic acid to form either the alcohol or alkane was
detected.[15c]
Several control experiments were conducted to obtain
information about the reaction mechanism (Scheme 2). First,
N-hexylbenzamide was tested under the same reaction
conditions, and it generated the amine product quantitative-
ly.[7b,c] When hexanal was used instead of hexanoic acid,
a mixture of mono- and dialkylation products was obtained in
low yields. When hexan-1-ol was used, no alkylation product
was obtained at all. It should be noted that when a carboxylic
acid with a bulky group adjacent to the carbonyl group were
À
tested, no C N bond-formation product was obtained.
Instead, only the reduced alkane product was obtained. It
should also be noted that according to the report by
Gevorgyan et al., reduction of carboxylic acid under B-
(C6F5)3/silane conditions does not proceed via an aldehyde
intermediate.[15c] These observations suggest the possibility
that the reaction proceeds through an amide intermediate,
and reducing the carboxylic acid to the aldehyde with
subsequent reductive amination is unlikely because of the
different selectivity observed. The unique catalytic activity of
À
acid was used, sequential reductive C N formation and SN2
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Scheme 4. One-pot, metal-free synthesis of Cinacalcet.
Scheme 5. One-pot, metal-free synthesis of Piribedil.
appealing from both an economic and environmental point of
view.
In conclusion, we have found that a boron-based catalyst
can catalyze straightforward alkylation of amines with
carboxylic acids in the presence of silane as a reducing
agent. Both primary and secondary amines can be smoothly
alkylated with good selectivity and good functional-group
compatibility. The application of this method was demon-
strated by the one-pot, metal-free syntheses of three drug
molecules, namely, Butenafine, Cinacalcet, and Piribedil.
Scheme 2. Control experiments: a) reduction of N-hexylbenzamide.
b) Reductive amination of hexanal. c) Using hexan-1-ol. d) Using
adamantane-1-carboxylic acid.
À
tris(perfluorophenyl)borane and the selective reductive C N
bond formation in preference to reduction of the carboxylic
acid suggests an FLP mechanism in which the boron and
carbonyl of the substrate form a FLP to activate the
silane[13b–d,17] and catalyze the reductive formation of the C
Keywords: alkylation · amines · boron · frustrated Lewis pair ·
synthetic methods
À
N bond.[18]
Considering the toxicity and cost of transition-metal
catalysts, the pharmaceutical industry desires synthetic
routes which avoid utilizing expensive and toxic transition
metals. We successfully applied this boron-catalyzed method
to the preparation of three commercialized drug molecules.
The three routes all solely rely on the boron-based catalyst,
and no metal was needed. As depicted in Scheme 3,
Butenafine, an antimycotic agent, can be prepared in two
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Received: April 28, 2015
Revised: May 26, 2015
Published online: July 6, 2015
9046 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9042 –9046