Reductive Alkylation of Amines with Carboxylic Ortho Esters

Article abstract of DOI:10.1002/adsc.202000510

We have demonstrated for the first time that carboxylic ortho esters could be used as an alkylating agent in the reductive alkylation of amines. A variety of amines, including amino acid esters, were alkylated affording mono-alkylated products with high selectivity in practical to high yields using standard heterogeneous catalysts. By applying acyclic ortho esters alkylation was completed at room temperature. (Figure presented.).

Full text of DOI:10.1002/adsc.202000510

Title: Reductive Alkylation of Amines with Carboxylic Ortho Esters
Authors: Renat Kadyrov and Konrad Moebus
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000510
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10.1002/adsc.202000510
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Reductive Alkylation of Amines with Carboxylic Ortho Esters
Renat Kadyrova,b*, Konrad Moebusb
a
Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, 25068 Řež, Czech Republic.
E-mail: kadyrov@iic.cas.cz
Evonik Resource Efficiency GmbH, Rodenbacher Chaussee 4, 63457 Hanau, Germany.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. We have demonstrated for the first time that
carboxylic ortho esters could be used as an alkylating agent
in the reductive alkylation of amines. A variety of amines,
including amino acid esters, were alkylated affording
mono-alkylated products with high selectivity in practical
Scheme 1. Aminolysis of ortho esters and subsequent
to high yields using standard heterogeneous catalysts. By
hydrogenolysis.
applying acyclic ortho esters alkylation was completed at
room temperature.
showed that commercially available morpholine (1a)
and methyl orthoformate (2a) could be efficiently
Keywords: Ortho esters; Amines; Alkylation;
converted into N-methylmorpholine. Furthermore,
Hydrogenation; Heterogeneous catalysis
the alkylation proceeded smoothly over almost every
hydrogenation catalyst such as Pd/C, Pt/C, Ru/C and
Rh/C. The hydrogen uptake finished in minutes at
110°C, 40 bar and using 5 mol% of p-toluenesulfonic
acid and 1 mol% of powder catalyst affording the
desired product in almost quantitative yield. As
shown Table 1, pyrrolidine (1b) and methyl L-
prolinate (1c) have been transformed into N-
pentylpyrrolidine (3b) and methyl N-methyl-L-
prolinate with very good to excellent yields (3c) over
all four powder catalyst using this method. Also N-
propyl-L-leucine ethyl ester (3d) was prepared in
good yields with very good selectivity toward
monoalkylation. The generality of this approach was
proven by smooth alkylation of a number of primary
and secondary amines, including aminoacids (Table
2). Remarkably, 3-pyrroline (1j), anilines (1f-1h) and
amino acid esters (1c, 1d, 1k-1n) could be alkylated
at room temperature by applying acyclic ortho esters.
The alkylation of diethyl L-glutamate (1m) at 60°C is
accompanied by intramolecular aminolysis with
formation of lactam (3o). The alkylation of aniline
(1e) with ethyl orthopropionate (2d) and pyrrolidine
(1b) with ethyl orthobenzoate (2e) give synthetically
useful to good yields at elevated temperatures. At
these conditions, the alkylation of benzylamine (1i)
gives dialkyated product (3j) in quantitative yields
using 3 equivalents of ethyl orthoformate (2a), while
mixture of mono- and dialkylation products formed
by using one equivalent of ortho ester. Furthermore,
alkylation of anilines (1f-1h) with ethyl orthoformate
(2a) proceed smoothly at room temperature in
presence of 5% Pt/C delivering the dialkylated
products (3f-3h) in quantitative yields. We have
shown that Pt/C catalyst in the alkylation of 3-
chloroaniline (1g) was recyclable with no appreciable
Amines are an interesting target in organic chemistry
with great potential in the pharmaceutical and fine
chemical industries. Reductive alkylation of ammonia,
primary or secondary amines with carbonyl
compounds constitutes one of the most convenient
and practical approaches for synthesis of higher
alkylated amines.[1] Using hydrogen as a reducing
agent is one of the powerful methods for carrying out
this transformation. Although diverse modifications
have been established, the development of catalytic
reduction with hydrogen continues to be one of the
greatest tasks as many publications over the last few
years show.[2] In the last years significant progress
has been achieved in reductive alkylation of amines
[9, 10]
using alcohols[3, 4], carboxylic acids[4-8] and CO2
as alkylating agents. Despite the advances made by
biocatalytic methods[4], by using borohydride[5, 7a] and
silanes[6, 7] as reducing agents catalytic hydrogenation
remains one of the major challenges.[7a, 8] Hence, the
development of milder and more selective methods
using commercially available heterogeneous catalysts
is of significant interest for the fine chemical and
pharmaceutical industries. Very recently, we have
demonstrated that hydrogenolysis of the amide
acetals and imido esters proceed at very mild
conditions
hydrogenation
over
commercially
Trialkyl
available
orhto
catalysts.[11]
carboxylates react with primary and secondary
amines in the presence of catalytic amounts of acid to
yield an amide acetal (Scheme1).[12] Therefore, it
appears likely that hydrogenation of a mixture of
ortho esters and amines in the presence of catalytic
amounts of an acid and hydrogenation catalyst should
give an alkylated amine. In fact, the first experiments
1
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10.1002/adsc.202000510
Advanced Synthesis & Catalysis
Table 1. Catalyst screening in reductive alkylation.a
Amine
Ortho Etser
Product
Catalyst
Timeb, h
Yieldc, %
5% Pd/C
5% Pt/C
5% Ru/C
5% RhC
5% Pd/C
5% Pt/C
5% Ru/C
5% Rh/C
5% Pd/C
5% Pt/C
5% Ru/C
5% Rh/C
5% Pd/C
5% Pt/C
5% Ru/C
5% Rh/C
0.3
0.2
92
97
96
98
81
95
90
86
98
99
98
97
82
75
71
85
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
0.25
0.25
0.8
0.25
0.25
0.1
0.5
OMe
H
0.15
0.25
0.25
1
OMe
OMe
0.1
0.6
0.2
a) Conditions: amine (5 mmol), ortho ester (6 mmol), catalyst (1 mol%), pTSA (5 mol%), 5 mL MeOH or EtOH, 40 bar
H2, 110 °C. b) Time required for completeness of hydrogen uptake. c) Products were isolated as hydrochlorides and yields
determined by GC analysis using tetradecane as an internal standard.
loss of activity for three repeated runs, indicating that
the catalyst is not only reusable but also has high
chemoselectivity toward alkylation. Applying Pd/C
and Rh/C as catalysts in the alkylation of 3-
Scheme 2. Straightforward method for synthesis of bicyclic
chloroaniline (1g) and 4-bromoaniline (1h) led to
ortho esters.[14,15]
predominant formation of cyclohexyldimethylamine -
product of hydrodehalogenation and aromatic ring
Many straightforward routes toward the preparation
of ortho esters are the subject of numerous reviews.[12]
The method outlined on Scheme 2 provides the
general method for preparation of ortho esters direct
from carboxylic acids. The latter method gives the
hydrogenation. By the alkylation of 4-bromoaniline
(1h) using Pt/C noticeable amounts of N,N-
dimethylaniline (product of hydrodehalogenation)
were detected in the reaction mixture.
In general, the hydrogenation of carbon-carbon
double bond is very rapid over the most
facile access to a variety of bicyclic ortho esters with
different substitution patterns.[14,
Generally, the
15]
hydrogenation catalysts.[1f] The
simultaneous
reaction of bicyclic ortho esters and aminoacids
proceeds smoothly at high temperature (100 °C) to
give good overall yield of the desired product after
hours by alkylation with 1-alkyl-4-methyl-2,6,7-
trioxabicyclo[2.2.2]octane (2g-2i). Even higher
temperature (120 °C) and heating for days (48-72 h)
are required for achieving good yields by alkylation
reduction of alkene units were observed at
hydrogenolysis of amide acetals over Pt/C.[11b] As
expected, also hydrogenation of double bonds in 3-
pyrroline (1j) and ortho ester (2g) were observed by
synthesis of amines (3b and 3p).
Recently we have shown that hydrogenolysis of
amideacetals proceed with high chemoselectity
without racemization of the neighboring chiral
center.[11] On the other site, amino-acids and their
esters can be racemized under acidic conditions,
although this requires strong acids and temperatures
well above 100°C.[13] We were very surprised to learn
that proline methyl ester (1c) racemizes in the
presence of an equimolar HCl in MeOH at room
temperature. In contrast, the racemization of alanine
(1k), leucine (1d) and phenylalanine (1l) esters
proceed at elevated temperatures (>100°C) in the
presence of an equimolar HCl in alcohol as described
in earlier studies.[13] It is therefore not surprising that
alkylation of these amino acid esters at room
temperature proceeds without racemization (see
Supporting Information). Partial racemization occurs,
however, by alkylation at 120°C at weak acidic
conditions.
with
4-methyl-2,6,7-trioxabicyclo[2.2.2]octane-1-
propanoic acid methyl ester (2j). The alkylation of
methyl L-leucinate (1p) at 120°C is accompanied by
intramolecular aminolysis with formation of lactam
(3s). Nevertheless, these examples show practical
usability of biciclyc ortho esters as alkylating agents
In conclusion, it was for the first time demonstrated
that carboxylic ortho esters could be used as an
alkylating agent in the reductive alkylation of amines.
The present method is especially useful for selective
monoalkylation of primary amines and methylation
under water-free conditions. Furthermore, the
developed method has several advantages, especially
as off-the-shelf catalysts could be utilized. By
applying acyclic ortho esters alkylation complete at
room temperature.
2
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10.1002/adsc.202000510
Advanced Synthesis & Catalysis
Table 2. Isolated yields in reductive alkylation with carboxylic ortho esters.a
Temperature Timeb Yieldc
Amine
Ortho Ester
Product
Catalyst
°C
h
%
5% Pt/C
pTSA
PhNH2
1e
1f
2d
2a
3e
3f
110
12
73d
5% Pt/C
TFA
25
25
4
4
99e
99e
5% Rh/C
TFA
5% Pt/C
TFA
1g
1h
2a
2a
3g
3h
25
25
4
4
99e
5% Pt/C
TFA
65e,f
5% Pt/C
pTSA
110
110
110
110
5
8
93
81
1b
1i
2e
2a
3i
3j
5% Rh/C
pTSA
5% Pd/C
pTSA
14
1
99e
99e
5% Pt/C
pTSA
5% Pt/C
TFA
1j
2b
2c
3b
3c
25
25
24
24
86
OMe
H
5% Pt/C
TFA
1c
83g
OMe
OMe
5% Pt/C
TFA
1k
2d
3k
25
24
79h
5% Pt/C
TFA
1d
1l
2d
2d
2f
3d
3l
25
25
25
24
24
28
85h
90h
92g
5% Pt/C
TFA
5% Pt/C
TFA
1m
3m
5% Pt/C
pTSA
1n
2a
2d
3n
3o
25
60
24
4
90
5% Pt/C
TFA
1m
91g
5% Pt/C
TFA
1b
1n
2g
2h
3p
3q
100
100
24
20
94
91
5% Pt/C
pTSA
5% Pt/C
pTSA
1o
1q
2i
2j
3r
100
120
1
82g
90g
COOMe
5% Ru/C
pTSA
3s
48
N
O
5% Ru/C
pTSA
1c
2j
3t
120
56
82g
12% Pt/C
pTSA
1q
1n
2j
2j
3u
3v
120
120
72
48
70
45
12% Pt/C
pTSA
EtOOC
N
COOEt
a) Conditions: amine (0.1 mol), ortho ester (0.12 mol), catalyst (0.5 mol%), pTSA or TFA (5 mol%), 30 mL MeOH or
EtOH, 40 bar H2. b) Time required for completeness of hydrogen uptake. c) Products were isolated by distillation in
vacuum or by column chromatography (see Supporting Information). d) 11% of PhN(n-Pr)2 and 4% of EtCONHPh were
detected in crude product after hydrogenation. e) 3 Equivalents of orthoformate was used; f) 30% of N,N-dimethylaniline
were detected in crude product after hydrogenation. g) The substrate was enantiomerically pure (>97% e.e.), the product
possesses a significant optical activity but the e.e. has not been determined. h) E.e. > 98% determined by integration of 19
NMR signals and GC peaks of MTPA amides.
F
3
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10.1002/adsc.202000510
Advanced Synthesis & Catalysis
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Experimental Section
A 100 ml autoclave was charged with catalyst (0.5 mol%)
and closed, autoclave repeatedly purged with nitrogen, then
a solution of amine (0.1 mol) and ortho ester (0.12 mmol in
30 ml of dry methanol/ethanol and freshly prepared water-
free solution of p-toluenesulfonic acid in methanol
(ethanol) (5 mmol) or trifluoroacetic acid (0.57 g, 5 mmol)
were added using syringe under nitrogen. The autoclave
was heated to desired temperature and pressurized to 40 bar
with hydrogen. After hydrogen uptake cased, autoclave
was allowed to cool down to ambient temperature and
depressurized, the catalyst was filtered through celite,
solids washed with methanol/ethanol, combined filtrates
concentrated on rotary evaporator and dissolved in 50 ml of
2N hydrochloric acid (cold) and washed with diethyl ether.
The aqueous layer was basified with 2N NaOH and
extracted with diethyl ether. Combined organic layers were
dried over K2CO3 and distilled in vacuum or purified by
column chromatography.
Acknowledgements
Authors thank Ralf Jantke and Stephan Weidlich for assistance
with hydrogenation experiments. Gudrun Welzel and Dr. Jens
Holz from Leibnitz Institute for Catalysis for measuring of optical
rotation and Dr. Ralf Jackstel for providing of HRMS spectra.
Also grateful to Sebastian Fuß for assistance in determination of
enantiomeric excess (e.e.) of the selected chiral compounds by
HPLC analysis.
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10.1002/adsc.202000510
Advanced Synthesis & Catalysis
COMMUNICATION
Reductive Alkylation of Amines with Carboxylic
Ortho Esters
Adv. Synth. Catal. Year, Volume, Page – Page
R. Kadyrov*, K. Moebus
6
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