Switching the N-Alkylation of Arylamines with Benzyl Alcohols to Imine Formation Enables the One-Pot Synthesis of Enantioenriched α-N-Alkylaminophosphonates

Article abstract of DOI:10.1002/ejoc.201900209

The selective N-alkylation of anilines with benzylic alcohols can be switched in favor of the dehydrogenative condensation process using the nitrile-ligated Kn?lker's complex by conducting the reaction either in a closed system under inert conditions, or in an open system in air. The selective formation of imines, containing reactive C=N bonds, provides an opportunity towards further functionalization. Indeed, a one-pot three-component condensation of alcohols, amines and phosphites, promoted by an iron-based Kn?lker-type complex in combination with a chiral BINOL-based phosphoric acid, provides access to enantioenriched α-N-alkylaminophosphonates.

Full text of DOI:10.1002/ejoc.201900209

A Journal of
Accepted Article
Title: Switching the N-Alkylation of Arylamines with Benzyl Alcohols
to Imine Formation Enables the One-Pot Synthesis of
Enantioenriched α-N-Alkylamino Phosphonates
Authors: Natalie Hofmann and Kai Hultzsch
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900209
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900209
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10.1002/ejoc.201900209
European Journal of Organic Chemistry
FULL PAPER
Switching the N-Alkylation of Arylamines with Benzyl Alcohols to
Imine Formation Enables the One-Pot Synthesis of
Enantioenriched -N-Alkylamino Phosphonates
Natalie Hofmann,[a] and Kai C. Hultzsch*[a]
Dedication ((optional))
Abstract: The selective N-alkylation of anilines with benzylic alcohols
can be switched in favor of the dehydrogenative condensation
process using the nitrile-ligated Knölker’s complex by conducting the
reaction either in a closed system under inert conditions, or in an open
system in air. The selective formation of imines, containing reactive
C=N bonds, provides an opportunity towards further functionalization.
Indeed, a one-pot three-component condensation of alcohols, amines
and phosphites, promoted by an iron-based Knölker-type complex in
combination with a chiral BINOL-based phosphoric acid, provides
access to enantioenriched -N-alkylamino phosphonates.
Iron is particularly attractive as it is one of the most abundant
metals in the earth crust. Besides, iron species are ubiquitous in
biological systems and metabolic processes making them
interesting for applications in the food and pharmaceutical
industry.[7] The low toxicity of iron is often used in the discussion
on iron-based catalysts as well; however, the toxicity level of iron
has to be viewed critically.[8] Knölker’s complex itself has been
applied in combination with different organocatalysts. Rodriguez
et al. established the enantioselective functionalization of allylic
alcohols by applying, among others, a triple iron/copper/iminium
activation,[3] whereas Beller et al. reported enantioselective
hydrogenations of imines and quinoxalines by combining iron
catalysis with chiral phosphoric acids 2.[4] In this work we focus on
the synthesis of enantioenriched -N-alkylamino phosphonates
by combining a hydrogen-borrowing based N-alkylation with the
Kabachnik-Fields reaction.[9] As α-amino phosphonates are
valuable replacements of α-amino carboxylic acids, which are
building blocks of proteins and peptides and therefore play an
important role in many physiological processes, their easy and
waste-free synthesis is of particular interest.[10] To the best of our
knowledge there are only two heterogeneous systems for the one-
pot condensation of anilines, alcohols and phosphites, but no
homogeneous system at all. On one hand Hosseini et al. reported
CuO@Fe3O4 nanoparticles to be suitable catalysts,[11] on the
other hand Fan and coworkers conducted the reaction with gold
supported on hydroxyapatite.[12] With this in mind we decided to
develop a homogeneous system to synthesize enantioenriched
-amino phosphonates. As Beller and coworkers could combine
the iron-based Knölker’s complex 1c with chiral phosphoric acids
2 for hydrogenations[4] and phosphoric acids are common
organocatalysts for hydrophosphonylations,[9b,13] we chose to
combine similar systems for the exploration of the
enantioselective one-pot condensation of anilines, alcohols and
phosphites. In the course of our investigations we found that it is
possible to control the selectivity of the N-alkylation of aniline
promoted by Knölker’s complex 1b and 1c by varying the reaction
conditions (Scheme 1).[14] So far, under base-free conditions iron
is known to favor the formation of the respective amine, whereas
manganese is prone to stop at the imine-intermediate.[15] In this
study we will show that a selective formation of the N-alkylated
amine can be achieved by conducting the reaction under argon,
whereas a selective imine formation is observed when the
reaction is performed under atmospheric conditions. The reactive
Introduction
The development of atom-efficient transformations that lead to
valuable compounds bearing carbon-heteroatom bonds starting
from innocuous and cheap starting materials is in the focus of
modern synthetic chemistry.[1] Therefore, hydrogen borrowing
catalysis is an important contemporary research topic as it
provides a green method for a variety of transformations of
alcohols, in particular the formation of new carbon-carbon or
carbon-nitrogen bonds.[2] In order to gain access to higher
functionalized products the combination of metal-based hydrogen
borrowing catalysis with organocatalysis provides promising
possibilities.[3–5] Our interest is primarily focused on different
derivatives of the well-known iron-based Knölker’s complex 1a–
1c (Figure 1).[6]
SiMe3
O
SiMe3
O
SiMe3
OH
SiMe3
CO
OC
1a
SiMe3
SiMe3
Fe
Fe
Fe
H
OC
OC
OC
OC
N
OC
1b
1c
R
2a R = H
2b R = 2,4,6-(iPr)3C6H2
2c R = 3,5-(CF3)2C6H3
2d R = 4-NO2C6H4
2e R = SiPh3
O
O
O
P
OH
2f R = 1-naphthalene
2g R = 9-anthracene
R
2
Figure 1. Applied metal and organocatalysts.
imine can subsequently undergo
a hydrophosphonylation
[a]
N. Hofmann, MSc., Univ.-Prof. Dr. K. C. Hultzsch
Universität Wien, Fakultät für Chemie,
Institut für Chemische Katalyse
Währinger Straße 38, 1090 Wien (Austria)
E-mail: kai.hultzsch@univie.ac.at
reaction leading to -N-alkylamino phosphonates. Therefore,
three different products are accessible starting from anilines and
benzylic alcohols simply by varying the reaction conditions and by
combining metal catalysis with organocatalysis.
https://chemcat.univie.ac.at/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900209
European Journal of Organic Chemistry
FULL PAPER
system in order to achieve good conversions to 4a. By changing
the solvent from toluene to the higher boiling p-xylene the
outcome was improved further. Despite these harsh conditions, a
practical feature is that the selective formation of the imine can be
conducted under atmospheric conditions, significantly simplifying
the reaction’s feasibility. Further investigations showed that the
application of molecular sieves (3 Å) is crucial for the success of
both reactions.
NH2
OH
+
Knölker's
complex
Open sy
Closed
system
stem
air)
(
(a
rgon)
N
N
H
Table 1. Selectivity studies for the N-alkylation of aniline with benzyl alcohol.
O
Chiral
phosphoric
acid
P
O
H
O
O
P
O
O
Conversion [%][a]
N
H
Cat. 1b
[mol%]
Open/
closed
Temp.
[°C]
Time
[h]
#
Overall
Amine
Imine
4a
3a
Scheme 1. Selective synthesis of N-alkylated amines, imines and -N-
alkylamino phosphonates.
1
2
3
4
5
6
7
5.0
5.0
5.0
7.5
7.5
7.5
7.5
closed
closed
open
100
110
110
110
140
140
140
24
24
48
48
48
55
55
93
quant.
47
92
>99
7
<1
<1
40
54
73
78
83
Results and Discussion
open
63
9
Selective N-alkylation. Initially, we started our investigations on
this topic using Knölker’s complex 1a (Figure 1),[6] which was
already successfully applied for the direct alkylation of amines
with alcohols.[14] However, applying this type of catalyst required
additional base or activation reagents to achieve any reactivity in
the N-alkylation of aniline. As our goal was to combine the N-
open
87
14
16
17
open
94
open[b]
quant.
alkylation with
a
subsequent hydrophosphonylation step
Reaction conditions: 150 mg molecular sieves (3Å), 0.250 mmol benzyl
alcohol, 0.250 mmol aniline, 0.3 mL toluene. Closed = reaction in closed vial
under an argon atmosphere. Open = reaction in opened vial in air at 60 °C for
15 min, then the vial was loosely capped in order for hydrogen to be able to
escape and heated to 140 °C for 55 h.
[a] Conversion was determined via GC/FID and GC/MS using mesitylene as
internal standard. [b] p-xylene was applied as solvent.
promoted by chiral phosphoric acids 2, we were searching for a
way to avoid the application of base. Thus, we decided to utilize
Knölker’s complex 1b,[6b] in which one CO ligand is replaced by
acetonitrile. This variant of Knölker’s complex is a known catalyst
for transfer hydrogenations of aldehydes, ketones and alkynes
using isopropanol as hydrogen source.[16] Feringa and coworkers
used this air-stable nitrile-ligated complex for the N-alkylation of
amino acids.[14f] Darcel et al. observed moderate activity in the
-alkylation of ketones with alcohols.[17] Fortunately, this catalyst
turned out to be highly active in our base-free benchmark reaction
with aniline and benzyl alcohol as well. Besides, we synthesized
the hydride derivative 1c of the Knölker’s complex,[6c, 18] which
proved to be active as well.
The change in product selectivity upon switching from a closed
system under argon to an open system in air can be attributed to
an oxidative quenching of the reduced Knölker’s complex by
oxygen, which bypasses the imine hydrogenation pathway
(Scheme 2).[19, 20]
To our delight we could control the selectivity of this reaction
simply by switching between a closed system under argon
atmosphere and an open system under atmospheric conditions
with both catalysts (1b and 1c, see Table S1 in supporting
information). Realization under inert conditions resulted in the
quantitative formation of N-benzylaniline (3a), whereas execution
in an open system in air led to the selective formation of N-
benzylideneaniline (4a). In general, the nitrile-ligated complex 1b
exhibits a higher reactivity and is easier to handle than 1c thanks
to its bench stability.[6b] Therefore, this catalyst was used for the
following screening and optimization reactions (Table 1).
We found that the application of 5 mol% of 1b at 110 °C in a
closed system under argon leads to a quantitative formation of 3a.
Higher catalyst loadings (7.5 mol%) and temperatures (140 °C)
as well as longer reaction times (55 h) are required in an open
Scheme 2. Proposed mechanism for the aerobic quench of 1c short-circuiting
the hydrogen borrowing N-alkylation.
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Table 2. Synthesis of amines and imines through coupling of various alcohols
with amines.
After optimization of the reaction conditions we explored the
functional group tolerance and the selectivity of the catalyst. We
applied benzylic alcohols and anilines with several electron-
donating and electron-withdrawing groups. (Table 2). Methyl and
methoxy substituents proved to be well tolerated leading to the
corresponding secondary amines (3b, 3c, 3f, 3g, 3i, 3j),
respectively imines (4b, 4c, 4f, 4g, 4i, 4j) in good to excellent
yields. The reaction of ortho-hydroxybenzyl alcohol with aniline,
preferentially led to the amine 3e under both reaction conditions,
while the respective imine 4e was only formed in small amounts.
Similar observations were made in the reaction of 2- and 3-
aminopyridine with benzyl alcohol to preferentially form amines 3k
and 3l, but here the overall conversion was also diminished. The
converse was noticed in the reaction of ortho-chlorobenzyl
alcohol with aniline (3d, 4d). The reaction of aniline with linear
aliphatic alcohols n-butanol, n-pentanol, and n-hexanol led to the
corresponding amines 3m–o in good yields, similar to
observations made by Kirchner et al. using an iron PNP pincer
catalyst;[14a] however, even under atmospheric conditions the
amines 3m–o remained the prevailing products and only trace
amounts of imines 4m–o were formed. Piperidine was completely
converted into the corresponding tertiary amine (3p) after
increasing the reaction temperature, which confirms the
observation by Feringa et al. that the catalyst is capable of
converting secondary amines as well.[14f] The exploration of an
intramolecular reaction with 2-aminophenethyl alcohol showed a
complete consumption of the starting material; however, only 36%
of 1H-indoline (3q) were formed and 1H-indole (4q) was detected
as the major product, independent of the reaction conditions.
Obviously, tautomerization of the imine intermediate is more facile
than reduction to 3q, driven by the rearomatization of 4q. The
reaction of benzyl alcohol with hexylamine produced amine 3r in
good yield under the closed system conditions, while under
atmospheric conditions a 1:1 mixture of amine 3r and imine 4r
was observed. The analogous reaction with benzylamine gave
the amine 3s preferentially under both sets of conditions.
(A) select. formation of amines 3
(B) select. formation of imines 4
With the knowledge that allylic alcohols have been successfully
applied in iron-catalyzed borrowing hydrogen N-alkylation[14e] and
cascade processes[3] and that imines derived from
cinnamaldehyde are well-suited for the enantioselective
hydrophosphonlyation with chiral phosphoric acids,[13] we decided
to subject allylic alcohols to our N-alkylation and imine formation
conditions (Table 3). The reaction of cinnamyl alcohol and crotyl
alcohol with either aniline or p-anisidine gave mixtures of 4
possible amine and imine products with or without ,-
unsaturation. Interestingly, the application of crotyl alcohol in a
closed system provided the fully saturated amines 3’t and 3’u as
major product, whereas cinnamyl alcohol led predominantly to the
,-unsaturated amines 3v and 3w. Under atmospheric
conditions the amount of ,-unsaturated imine 4t–w significantly
increased for all substrates, although the selectivity remained
moderate.
Reaction conditions:
A) selective formation of amine: 5 mol% 1b, 150 mg molecular sieves (3Å),
0.250 mmol alcohol, 0.250 mmol aniline, 0.3 mL p-xylene, 110 °C, 24 h, closed
system, argon.
B) selective formation of imine: 7.5 mol% 1b, 150 mg molecular sieves (3Å),
0.300 mmol alcohol, 0.250 mmol aniline, 0.3 mL p-xylene, 140 °C, 55 h, open
system, air.
Conversions and product ratios were determined via GC/FID and GC/MS using
mesitylene as internal standard. Amine/imine-ratios for all reactions are listed in
the supporting information in Tables S3A and S3B.
[a] NMR-yield. [b] Reaction temperature: 130 °C. [c] The identity of the products
was verified by 1H-NMR spectroscopy. [d] Reaction time: 92 h.
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10.1002/ejoc.201900209
European Journal of Organic Chemistry
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phosphite gave essentially a racemic product. This observation
can be explained by a fast uncatalyzed background reaction for
this substrate. The reaction is complete within 15 min even in the
absence of an acid catalyst. In order to rule out a radical process,
the reaction of diphenyl phosphite with 4a was repeated in the
presence of 1 equiv hydroquinone with and without added
phosphoric acid 2a, leading also to complete conversion within
15 min in both cases.
Table 3. Investigation of allylic alcohols in the N-alkylation and imine
formation.
Table 4. Influence of the acid catalyst, structure of phosphite and reaction
temperature on the enantioselective hydrophosphonylation of imine 4a.
Conversion [%][a]
#
R
Ar
Overall
3
3’
4
4’
(A) closed system under argon
1
2
3
4
CH3
CH3
Ph
Ph
PMB
Ph
>99
>99
>99
>99
2
3
83
48
30
17
2
33
9
13
16
<1
<1
Temp.
[°C]
Yield
[%][a]
ee
#
Product
2
HP(O)(OR)2
[%][b]
Different phosphoric acids 2
61
68
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
---
2a
2b
2c
2d
2e
2f
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
25
25
25
25
25
25
25
25
21
94
--[c]
<5
23
52
9
Ph
PMB
15
(B) open system in air
91
5
6
7
8
CH3
CH3
Ph
Ph
PMB
Ph
>99
94
2
3
43
31
5
50
53
39
38
5
8
93
89
90
46
47
<1
<1
84[d]
90
45
8
Ph
PMB
95
10
Reaction conditions:
A) selective formation of amine: 5 mol% 1b, 150 mg molecular sieves (3Å),
0.250 mmol alcohol, 0.250 mmol aniline, 0.3 mL p-xylene, 110 °C, 24 h, closed
system, argon.
2g
91
35
B) selective formation of imine: 7.5 mol% 1b, 150 mg molecular sieves (3Å),
0.300 mmol alcohol, 0.250 mmol aniline, 0.3 mL p-xylene, 140 °C, 24 h, open
system, air.
[a] Conversions and product ratios were determined via GC/FID and GC/MS
using mesitylene as internal standard.
Different phosphites
9
5aa
5ab
5ac
2c
2c
2c
HP(O)(OMe)2
HP(O)(OiPr)2
HP(O)(OPh)2
25
25
25
91
95
47
39
<5
10
11
98[e]
Enantioselective hydrophosphonylation. In order to promote
the enantioselective hydrophosphonylation, we focused on chiral
phosphoric acids, which are known to be efficient organocatalysts
for various selective additions to imines,[21] including the
hydrophosphonlyation.[9b, 13] Akiyama[13a, 13b] and Ma[13c] studied
the enantioselective hydrophosphonlyation of N-benzylidene p-
anisidine and aldimines derived from cinnamaldehyde derivatives
using the BINOL-based phosphoric acids 2a–g. As a test reaction,
we therefore decided to investigate the addition of various
phosphites to N-benzylideneaniline (4a) (Table 4).
In general, decent yields were obtained for all phosphoric acids
and phosphites, while enantioselectivities remained moderate. In
agreement to results obtained for N-benzylidene p-anisidine,[13]
the sterically hindered 3,5-bis(trifluoromethyl)phenyl-substituted
acid 2c gave the highest selectivity (52% ee). Despite its
bulkiness, the anthracene-substituted phosphoric acid 2g was
significantly less enantioselective (35% ee). Interestingly, the
sterically more demanding diisopropyl and diphenyl phosphite led
to a diminished enantioselectivity as well. In particular, diphenyl
Varying temperatures
12
13
14
5a
5a
5a
2c
2c
---
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
0
91[f]
95[g]
94
51
47
<5
60
100
Reaction conditions: 5 mol% 2, 0.250 mmol N-benzylideneamine,
0.275 mmol phosphite, 0.3 mL toluene.
[a] Isolated yield. [b] Determined via chiral HPLC. [c] Not applicable.
[d] Reaction time: 48 h. [e] The reaction proceeded to completion within
15 min also in the absence of an acid catalyst or when 1 equiv hydroquinone
(relative to 4a) was added. [f] Reaction time: 90 h; [g] Reaction time: 5 h.
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Varying the reaction temperature solely influenced the rate of the
reaction, but hardly showed any impact on the enantioselectivity
(Table 4, entries 4, 12, 13). Lower reaction temperatures required
longer reaction times, whereas higher temperatures led to a faster
completion of the reaction. In general, the addition of diethyl
phosphite to the imine proceeded also in the absence of catalyst
when the reactions were conducted at 100 °C.
Table 5. One-pot two step synthesis of -amino phosphonates 5
Attempts to extend the substrate scope of the enantioselective
hydrophosphonlyation of imines to the aliphatic imine N-
phenylhexanimine were frustrated by its instability in the presence
of either diethyl phosphite (pKA ≈ 13.0)[22a] or chiral phosphoric
acid (pKA ≈ 3.0),[22b] leading to facile cleavage of the imine.
One-pot synthesis of -N-alkylamino phosphonates. Since
we
wanted
to
couple
the
N-alkylation
with
the
hydrophosphonylation, we performed compatibility studies as well.
We found that aniline hampers the addition of diethyl phosphite to
N-benzylideneaniline, whereas phosphoric acids 2 suppress the
N-alkylation. This led us to the conclusion that a one-pot cascade
reaction is not feasible, but the synthesis of -N-alkylamino
phosphonates can be achieved in a sequential one-pot procedure
(for detailed experimental data see supplementary information,
Tables S4 and S5). With the optimized reaction conditions for
each reaction step, we were able to carry out the synthesis of
diethyl (phenyl(phenylamino)methyl)phosphonate (5a) in 80%
isolated yield with 50% ee via one-pot condensation of aniline,
benzyl alcohol and diethyl phosphite (Table 5). Fractional
crystallization of rac-5a was observed during recrystallization
from heptane, leaving the enantioenriched form in the
supernatant and increasing the enantiomeric excess up to 81%.
However, none of the other products showed
fractionation.
a similar
After showing the proof of principle with the benchmark reaction,
we chose suitable substrates to investigate the influence of steric
and electronic changes on the hydrophosphonylation. We found
that steric hindrance in the ortho-position, either in the alcohols or
the amines, did not improve the selectivity of the reaction and the
enantiomeric excess remained in the 30–40% range in most
cases. However, the addition of diethylphosphite to the imines
derived from ortho-methyl- and ortho-fluoro-aniline were
hampered and no reaction was observed at ambient temperature.
Only heating to 60 °C, respectively 100 °C, produced the desired
products 5g and 5h in decent yields.
Reaction conditions: 1) 7.5 mol% 1b, 150 mg molecular sieves (3Å),
0.300 mmol alcohol, 0.250 mmol aniline, 0.3 mL p-xylene, open system, air; 2)
10 mol% 2c, 0.275 mmol phosphite; Isolated yields.
[b] Determined via chiral HPLC. [c] Reaction temperature: 60 °C. [d] Reaction
temperature: 100°C.
Conclusions
In brief, the N-alkylation of anilines with benzylic alcohols
catalyzed by the highly reactive acetonitrile-ligated Knölker
complex 1b can be switched in favor of imine formation. While the
borrowing hydrogen process is achieved in a closed system under
argon, the dehydrogenative condensation occurs at a higher
temperature in an open system in air. Both reactions do not
require activation by a base additive. The highly reactive C=N-
bond of the in situ formed imine can be used for the atom-efficient
synthesis of -N-alkylamino phosphonates by a one-pot three-
component condensation of alcohols, amines and phosphites.
Notably, this tandem reaction can be performed under
atmospheric conditions, forming water as the only by-product and
the applied chiral phosphoric acid can be recovered. However,
this protocol appears to be only amenable to aniline and benzyl
alcohol derivatives, as aliphatic alcohols and amines either lead
to predominant amine formation under both sets of reaction
During purification of products 5a–5j we managed to recover the
valuable chiral phosphoric acid catalysts 2 from the last fraction
of the column chromatography.
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Synthesis of diethyl (phenyl(phenylamino)methyl) phosphonate (5a).
In a PTFE-lined screw-cap vial (1.5 mL), equipped with a magnetic stirring
bar and molecular sieves (3 Å, 150 mg), Knölker’s complex 1b (8.1 mg,
0.019 mmol, 0.075 equiv) was dissolved in p-xylene (0.3 mL). Then benzyl
alcohol (31 µL, 1.04 g/mL, 0.300 mmol, 1.2 equiv) and aniline (23 µL,
1.03 g/ml, 0.250 mmol, 1.0 equiv) were added. The vial was placed in an
aluminum block and the resulting reaction mixture was heated in the vial
opened to air to 60 °C with magnetic stirring for 15 min, then the vial was
loosely capped in order for hydrogen to be able to escape, covered with
aluminum foil, and heated to 140°C for 55 h. After cooling to room
temperature, chiral phosphoric acid 2c (19.3 mg, 0.025 mmol, 0.10 equiv)
was added, followed by the addition of HP(O)(OEt)2 (35 µL, 1.07 g/mL,
0.275 mmol, 1.1 equiv). The mixture was stirred for additional 24 h at
ambient temperature. The reaction was quenched by addition of sat.
NaHCO3-solution (0.5 mL) and the water layer was extracted with EtOAc
(3 × 3 mL). The combined organic layers were dried over MgSO4 and the
solvent was removed under vacuum. Purification via column
chromatography (silica, 20–50% EtOAc in heptane, 0.5% Et3N) led to
64 mg (81%) of diethyl (phenyl(phenylamino)-methyl)phosphonate as
white solid.
conditions or the resulting aliphatic imines are unstable under the
conditions of hydrophosphonylation.
Experimental Section
General considerations. Toluene and p-xylene were distilled from
sodium benzophenone ketyl. Alcohols and phosphites used as substrates
for catalysis were distilled from Na2SO4. Amines used as substrates for
catalysis were distilled from CaH2. If not mentioned differently all
commercially available starting materials were used without further
purification. All 1H, 13C, 31P, and 19F NMR spectra were recorded on a
Bruker UltrashieldTM 400 or 600 Plus instrument, whereby the 1H NMR
spectra were measured at 400.3 MHz or 600.2 MHz, the 13C NMR spectra
at 100.6 or 150.9 MHz, and the 31P NMR spectra at 162.0 MHz. All
chemical shifts are noted in ppm. 1H and 31C chemical shifts are indicated
relative to TMS and were referenced to residual signals of the solvent (1H
NMR (CDCl3): 7.27 ppm, 13C NMR (CDCl3): 77.0 ppm). 31P chemical shifts
were referenced to H3PO4 (0.00 ppm). Column chromatography was
performed by using Biotage® SP4 and Isolera flash systems and the
applied columns were packed with silica gel 60 Å or aluminium oxide 90
standardised (activity II-III). TLC was performed with commercial Kieselgel
60 F254 or ALOX N/UV254 and visualized via UV lamp. GC/MS
measurements were conducted on an Agilent Technologies with 5977B
MSD High Efficiency Source and 7820A GC-system. GC/FID
measurements were conducted on a Shimadzu GC-2010 system. HPLC
measurements were conducted on an Agilent Technologies Series 1200
system with 61379B Degasser, 61311A QuatPump, 61329A LLS, 61316A
TCC, G1315D DAD. The Knölker’s complexes 1a,[14d] 1b,[6b,16a,16b] and
1c[6c, 18] were synthesized according to the literature, as well as the chiral
BINOL-based phosphoric acids 2a,[23] 2b,[23] 2c,[23] 2d,[24] 2e,[25] 2f,[26] and
2g.[27]
Acknowledgments
We would like to thank Mr. Adam ElBataioui for the synthesis of
phosphoric acids 2d and 2f and intermediates for 2g.
Keywords: hydrogen borrowing catalysis • organocatalysis •
tandem catalysis • -amino phosphonates • chiral phosphoric
acids
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10.1002/ejoc.201900209
European Journal of Organic Chemistry
FULL PAPER
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
The base-free N-alkylation of anilines
with benzylic alcohols can be
switched in favor of imine formation
simply by switching between a closed
and an open reaction system. Further
functionalization of the in situ
synthesized imine leads to -N-
alyklamino phosphonates via a one-
pot procedure in an atom-economic
fashion.
Key Topic*
Hydrogen Borrowing Catalysis,
Organocatalysis
Natalie Hofmann, Kai C. Hultzsch*
Page No. – Page No.
Switching the N-Alkylation of Arylamines
with Benzyl Alcohols to Imine Formation
Enables the One-Pot Synthesis of
Enantioenriched -N-Alkylamino
Phosphonates
*one or two words that highlight the emphasis of the paper or the field of the study
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