Ionic liquid-supported aldehyde: A highly efficient scavenger for primary amines

Article abstract of DOI:10.1021/co200151n

Novel aldehyde-functionalized ionic liquids have been synthesized and used as scavengers for primary amines in the synthesis of secondary amines. The yields of secondary amines are high (82-90%) with high purity. The advantages of the protocol over that w

Full text of DOI:10.1021/co200151n

Letter
pubs.acs.org/acscombsci
Ionic Liquid-Supported Aldehyde: A Highly Efficient Scavenger for
Primary Amines
Manoj Kumar Muthayala and Anil Kumar*
Department of Chemistry, Birla Institute of Science and Technology, Pilani, 333031 Rajasthan, India
S
* Supporting Information
ABSTRACT: Novel aldehyde-functionalized ionic liquids
have been synthesized and used as scavengers for primary
amines in the synthesis of secondary amines. The yields of
secondary amines are high (82−90%) with high purity. The
advantages of the protocol over that with a polymer-supported
aldehyde scavenger are the shorter reaction time, the
homogeneous reaction medium, the high level of loading of
the aldehyde group, easy monitoring of reaction, and characterization of intermediates.
KEYWORDS: ionic liquid, functionalized ionic liquid, scavenger, reductive amination, secondary amines
ombinatorial synthesis is a very useful technique for the
rapid synthesis of a library of compounds in the quest for
electrophiles in solution-phase parallel synthesis. Cai et al.22
has used a new diol-functionalized 2,2-bis[1-(1-
methylimidazolium)]methylpropane-1,3-diol hexafluorophos-
phate as a scavenger for aldehydes. They have also used
carboxyl-functional ionic liquid [cmmim][PF6] as a scavenger
C
pharmaceutically active compounds.1,2 In parallel synthesis,
when two or more reagents are being coupled, one reagent is
used in excess to drive the reaction to completion. Purification
in combinatorial chemistry is an interesting and often
challenging process. To remove the excess reagent or
byproduct in parallel synthesis, most commonly an immobilized
scavenger is added to the reaction mixture. Scavengers are the
materials that scavenge or quench a particular excessive reagent
or byproduct in the reaction mixture. Polymer-supported
scavengers are most commonly used in combinatorial synthesis.
Simple filtration removes polymer-supported scavengers to give
pure product, thus avoiding column chromatography.3−5
However, there are some downsides with these scavengers.
First, one has to use an excess of resin-bound scavengers
because of the ratio of less functional groups to polymer. In
addition, because of the biphasic system of the reaction
medium, rates of reaction are considerably slower than those of
the solution-phase system. To fulfill the swelling requirement of
polymer-supported reagents, one has to use large amounts of a
suitable solvent. Several alternative, e.g., PEG-supported,6 silica-
supported,7 fluorous-phase,8−10 and aqueous-phase,11,12 scav-
engers have been developed to overcome some of these
limitations of traditional polymer-supported scavengers.
for benzyl chloride, amines, and methanesulfonyl chlorides.23
A
commercial process of biphasic acid scavenging has been
developed by Maase and Massonne.24 Lei et al. used a water-
soluble 1-(2-aminoethyl)pyridinium bromide as a scavenger for
the solution-phase synthesis of amides and sulfonamides.25 The
main objective here is to reduce waste generation, minimize
solvent requirement, and optimize scale-up potential. Easy
monitoring and time saving have made the FILs more favorable
than polymer-supported scavengers.
On the other hand, reductive amination is a powerful tool for
the synthesis of structurally diverse secondary amines that are
used in high-throughput syntheses toward compound libraries
of potential drug candidates. In continuation of our efforts to
explore the synthetic utility of the ionic liquid and to develop
new and ecofriendly reaction methodologies,26−29 herein, we
report synthesis of a novel ionic liquid-supported aldehyde and
its use as a scavenger to remove primary amines in the synthesis
of secondary amines in the solution phase.
Synthesis of two different aldehyde-functionalized ionic
liquids is achieved as shown in Scheme 1. Reaction of 4-
hydroxybenzaldehyde (1) with 1-chloro-3-bromopropane (2)
in the presence of sodium bicarbonate gave monoalkylated
aldehyde 3. Reaction of 3 with N-methylimidazole (4) at 80 °C
gave the corresponding chloride salt (5). Anion exchange of 5
with KPF6 and NaBF4 resulted in corresponding ionic liquids
6a and 6b, respectively.
Because of specific chemical and physical properties, ionic
liquids (ILs) have received considerable attention for
applications in organic transformations. For example, ILs can
be used in catalysis, electrochemistry, liquid/liquid extractions,
purification processes, and organic synthesis. Physical proper-
ties of ionic liquids such as viscosity, hydrophobicity, melting
point, and solubility can be fine-tuned by changing the anions
and altering the length of the alkyl groups on the cations.13
Functionalized ionic liquids (FILs)14−20 have been used as
scavengers in parallel synthesis. Song et al.21 used [2-
aemim][PF6] ionic liquid as a scavenger for trapping
Received: August 20, 2011
Revised: November 4, 2011
Published: November 7, 2011
© 2011 American Chemical Society
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Letter
Scheme 1. Synthesis of Ionic Liquid-Supported Aldehydes 6a
and 6b
Table 1. Yields of Ionic Liquid-Supported Imines
a
entry
R′
imines
yield (%)
b
1
2
3
4
5
6
7
C6H5
8a
8b
8c
8d
8e
8f
87 (60)
87 (52)
86
c
4-ClC6H4
4-BrC6H4
4-IC6H4
4-CH3OC6H4
C10H7
86
89
85
C4H9
8g
70
a
b
c
Isolated yield. In the absence of 0.1 mol % acetic acid. Isolated yield
when 6b was used.
Scheme 2. Capture of Amines Using 6a
1
The structure of 6a and 6b is confirmed by H NMR and
1
high-resolution mass spectrometry. The H NMR spectrum
showed a singlet at δ 9.84 for the aldehydic proton, a singlet at
δ 3.82 for the methyl protons of N-methyl, two triplets and a
multiplet at 4.39, 4.14 and 2.35 ppm for OCH2, NCH2 and
CH2, respectively, and other aromatic protons of imidazolium
and the aryl ring. In the ESI-MS spectrum, a peak appeared at
245.13 [M − PF6]+ or [M − BF4]+ for both 6a and 6b.
After synthesizing ionic liquid-supported aldehydes 6a and
6b, we studied their scavenging properties by reacting them
with p-chloroaniline (7b) under different conditions. Only 60%
of 8b was obtained when 7b was reacted with 6a in methanol
under reflux conditions after 6 h. Adding a catalytic amount of
acetic acid dramatically increased the yield of 8b to 87% in 4 h
at room temperature. The imine of 6a (8b) precipitates out in
methanol (Figure 1B), whereas the imine of 6b was completely
in methanol and were removed by filtration; however, for n-
butylamine (7g), the ionic liquid-supported imine (8g) was
liquid and did not precipitate in methanol. In this case,
methanol was evaporated and excess amine was removed by
extraction with ethyl acetate, leaving behind 8g.
Next, the application of 6a as a scavenger for primary amines
was demonstrated in the parallel synthesis of secondary amines.
4-Chlorobenzaldehyde (9a) was reacted with excess 4-
chloroaniline (7b) in methanol to give the imine, which was
then reduced to N-(4-chlorobenzyl)-4-chlorobenzenamine
(11) via addition of NaBH(OAc)3. After completion of the
reduction of imine, an excess of 7b was removed by
precipitation of 8b upon reaction with 6a (Scheme 3). Using
Scheme 3. Synthesis of Secondary Amines Using 6a as s
Scavenger
Figure 1. Capture of 7b in 6a and 6b: (A) only methanol and 7b, (B)
methanol with 7b and 6a, and (C) methanol with 7b and 6b.
soluble in methanol (Figure 1C). Thus, simple filtration and
washing with appropriate solvents separated 8b from the
reaction mixture when 6a was used. The isolated yield of 8b
was 52% when 6b was used (Table 1, entry 2). Reaction of
seven different amines (7a−g) with 6a was studied to give
corresponding ionic liquid-supported imines (8a−g) (Scheme
2). The structure of ionic liquid-supported imines was
this methodology, a small library of secondary amines was
synthesized. The yield and purity of different secondary amines
(10−21) are listed in Table 2. All the synthesized secondary
amines were characterized by 1H NMR and 13C NMR
spectroscopic data (Supporting Information). The method is
1
confirmed by H NMR and 13C NMR analysis (Supporting
Information). In all aromatic amines (7a−f), the corresponding
ionic liquid-supported imines (8a−f, respectively) precipitated
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Letter
Table 2. Synthesis of Secondary Amines Using 6a as a
Scavenger
Scheme 4. Reuse of 6a as a Scavenger
EXPERIMENTAL PROCEDURES
■
Synthesis of Ionic Liquid-Supported Aldehydes (6a
and 6b). A mixture of 3 (0.025) and 1-methylimidazole
(0.027 mol) was heated at 80 °C for 6 h to give a thick viscous
liquid. The viscous liquid was washed with ethyl acetate (2 × 10
mL) to remove unreacted starting materials to give pure
chloride salt. Ion exchange of chloride was performed in dry
acetone (50 mL) using potassium hexafluorophosphate (0.041
equiv) for 6a or sodium tetrafluoroborate (0.041 equiv) for 6b
at room temperature for 48 h. After complete exchange of
chloride anion as indicated by silver nitrate, acetone was
evaporated. In the case of 6a, the resulting solution was washed
with water to remove salts and the ionic liquid was extracted
with dichloromethane (DCM) (3 × 50 mL), dried with
anhydrous sodium sulfate, and evaporated under reduced
pressure to yield pure 6a (4.30 g, 90%). In the case of 6b, the
reaction mixture was dissolved in DCM, and salts were
removed by repeated filtrations through 60−120 mesh silica gel
columns. Finally, DCM was evaporated to yield pure 6b (3.86
g, 93%).
6a: white solid; mp 92−95 °C; 1H NMR (300 MHz,
DMSO) δ 9.85 (s, 1H), 9.03 (s, 1H), 7.86 (d, J = 8.78 Hz, 2H),
7.75 (s, 1H), 7.65 (s, 1H), 7.05 (d, J = 8.78 Hz, 2H), 4.39 (t, J
= 7.0 Hz, 2H), Hz, 2H), 4.14 (t, J = 6.2 Hz, 2H), 3.85 (s, 3H),
2.35−2.26 (m, 2H); 13C NMR (101 MHz, DMSO) δ 191.9,
163.6, 137.22, 132.36, 130.18, 124.10, 122.92, 115.31, 65.51,
46.92, 36.07, 29.28; ESI-MS m/z calcd for C14H17F6N2O2P
390.0932, found 245.1302 [M − PF6]+.
a
b
c
Isolated yield. Purity determined by HPLC. Yields of 13 in the
second and third cycle were 80 and 78%, respectively.
simple and gives high yield of secondary amines with high
purities in a shorter reaction time. Guino et al. used polymer-
́
supported aldehyde as a scavenger for the synthesis of a small
library of secondary amines, and it took ∼3 days to complete
the process;30 with our method, the synthesis and purification
process was complete in 9−10 h.
To reuse ionic liquid-supported aldehyde 6a, we regenerated
it via treatment with a 2 N HCl solution after filtration from the
reaction mass (Scheme 4). The regenerated 6a was reused for
scavenging of aniline 7d three times without much loss of
activity (Table 2, entry 4).
In conclusion, we have synthesized a novel aldehyde-
functionalized ionic liquid and used it as a scavenger for
primary amines in the synthesis of secondary amines. The
yields of secondary amines are high (82−90%) with high purity.
The ionic liquid-supported aldehyde is a highly efficient
scavenger for the primary amines, and the time required for
the complete process using this scavenger is shorter than that
for the polymer-supported aldehyde scavenger.
6b: white solid; mp 51−52 °C; 1H NMR (300 MHz,
DMSO) δ 9.84 (s, 1H), 9.06 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H),
7.74 (s, 1H), 7.64 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 4.37 (t, J =
6.9 Hz, 2H), 4.16 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.34−2.26
(m, 2H); 13C NMR (101 MHz, DMSO) δ 191.94, 163.59,
137.17, 132.31, 130.23, 124.05, 122.86, 115.32, 65.54, 46.81,
36.15, 29.31; ESI-MS m/z calcd for C14H17BF4N2O2 332.1319,
found 245.1298 [M − BF4]+.
General Procedure for the Synthesis of Ionic Liquid-
Supported Imines. A mixture of ionic liquid-supported
aldehyde (6a or 6b) (0.0025 equiv) and amine (7a−g)
(0.003 equiv) in methanol in the presence of 0.1% acetic acid
was stirred for 4 h at 30 °C. In the case of 6a, a solid
precipitated and was filtered and washed with methanol to yield
the pure compound. For 6b, it was soluble in methanol, and
thus, the solvent was evaporated and the residue obtained
washed with ethyl acetate (3 × 15 mL) to yield the pure
compound.
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8a: mp 151−154 °C; 1H NMR (500 MHz, DMSO-d6) δ 9.13
(s, 1H), 8.54−8.49 (m, 1H), 7.90−7.86 (m, 2H), 7.79 (t, J =
2.0 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.42−7.35 (m, 2H),
7.24−7.18 (m, 3H), 7.04−7.00 (m, 2H), 4.36 (t, J = 6.9 Hz,
2H), 4.11 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.34−2.26 (m, 2H);
13C NMR (126 MHz, DMSO-d6) δ 161.23, 160.22, 152.16,
137.19, 130.90, 129.63, 129.60, 126.04, 124.05, 122.89, 121.35,
115.13, 65.27, 46.86, 36.18, 29.40; ESI-MS m/z calcd for
C20H22F6N3OP 465.1405, found 320.1789 [M − PF6]+.
General Procedure for Solution-Phase Synthesis of
Secondary Amines. Substituted benzaldehyde (1 mmol) and
amine (1.5 mmol) were added to a round-bottom flask
containing methanol (3.0 mL) and stirred for 2 h at room
temperature. Sodium triacetoxyborohydride (0.75 equiv) was
added to the reaction mixture and the mixture stirred for an
additional 30 min. After completion of reductive amination, 6a
(2 equiv) and 0.1 mol % acetic acid were added to the reaction
mixture, and the mixture was stirred for an additional 4 h. After
completion of the reaction as indicated by TLC, the solid was
filtered and the resulting solution was evaporated to yield the
pure secondary amine.
General Procedure for Regeneration of Ionic Liquid-
Supported Aldehyde (6a). To the ionic liquid-supported
imines (8d) (50 mg) was added 2 N HCl (1.0 mL), and the
mixture was stirred vigorously for 4 h. While the reaction
progressed, the color of the ionic liquid amine changed from
colorless to yellowish. After completion of the reaction, the
reaction mixture was neutralized with NaHCO3 and the
compound was extracted with DCM (3.0 mL). The organic
layer was dried with sodium sulfate and evaporated and
extracted with a hexane/ethyl acetate mixture (1:1, v/v) to
remove 4-iodoaniline (7d). After removal of 7d, the residue was
dried under reduced pressure to yield the ionic liquid aldehyde
(6a). The yield was 28 mg (85%).
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental details, 1H and 13C NMR data of
compounds 10−21, copies of NMR spectra for compounds
3, 6a, 8a−g, and 10−21, experimental procedures for synthesis
of 4-(3-chloropropoxy)benzaldehyde (3), and characterization
data for compounds 8b−8g. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Department of Chemistry, Birla Institute of Technology and
Science, Pilani, Rajasthan, India, PIN-333 031. Phone: +91-
1596-245073. Fax: +91-1596-244183. E-mail: anilkumar@bits-
pilani.ac.in.
Funding
We thank the Council of Scientific and Industrial Research
(CSIR), New Delhi [01(2214)/08/EMR-II], for financial
support.
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simple, and recoverable “capture and release” reagent for aldehydes.
Monatsh. Chem. 2009, 140, 39−44.
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Carboxyl-functional ionic liquids as scavengers: Case studies on benzyl
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liquids: The first commercial process with ionic liquids. In Ionic Liquids
IIIb: Fundamentals, Progress, Challenges, and Opportunities; American
Chemical Society: Washington, DC, 2005; Vol. 902, pp 126−132.
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