KOH-mediated transition metal-free synthesis of imines from alcohols and amines

Article abstract of DOI:10.1039/c2gc35714c

The various imines were prepared from alcohols and amines in moderate to good yields under an air atmosphere promoted by KOH, eliminating the need for toxic transition metal catalysts. Due to its simplicity, this protocol will have wide application in synthesis.

Full text of DOI:10.1039/c2gc35714c

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Green Chemistry
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COMMUNICATION
KOH-mediated transition metal-free synthesis of imines from alcohols and
amines†
Jian Xu, Rongqiang Zhuang, Lingling Bao, Guo Tang* and Yufen Zhao
Received 10th May 2012, Accepted 19th June 2012
DOI: 10.1039/c2gc35714c
the synthesis of imines was not yet known. We have previously
observed a trace amount of β-alkylation of lactic acid with
primary alcohols in the presence of KOH but without a transition
metal catalyst,13 in which the “KOH-promoted dehydrogenative
oxidation of alcohols” was the most crucial step in the reaction
pathway. On the basis of this concept, an 85% yield of benzoic
acid was obtained when benzyl alcohol (3.0 mmol) and KOH
(3.0 mmol) was heated in toluene at 110 °C for 40 h under
aerobic conditions. It was suggested that this might provide an
efficient approach for base-mediated reactions of amines with
carbonyls that should rely on the dehydrogenation of alcohols.
The various imines were prepared from alcohols and amines
in moderate to good yields under an air atmosphere pro-
moted by KOH, eliminating the need for toxic transition
metal catalysts. Due to its simplicity, this protocol will have
wide application in synthesis.
Introduction
The development of environmentally benign, tandem and cross-
coupling strategies is an important goal in contemporary organic
synthesis because of economy and environmental impact. In
recent years, a part of this drive is to avoid or minimize the use
of noble metals in tandem cross-coupling reactions, as these are
sometimes toxic, expensive and difficult to dispose off properly
in large quantities.
Results and discussion
To test this hypothesis, benzyl alcohol (1a) and aniline (2a) were
used as the substrates in these studies. When a mixture of 1a
(3.6 mmol) and 2a (3.0 mmol) and KOH (6.0 mmol) was heated
in toluene at 110 °C for 20 h under aerobic conditions. The reac-
tion gave the desired product, N-benzylideneaniline (3a), in 92%
yield (1H NMR yield) (Table 1, entry 1). The structure of 3a was
Imines are frequently found as substructures in a diverse array
of compounds, including a wide range of natural products, bio-
logically and therapeutically active substances.1 Imines are also
of great importance as intermediates in the synthesis of various
useful organic compounds.2 Therefore making them efficiently
is of paramount importance. The conventional methods for the
synthesis of imines involve the condensation of a primary amine
with a carbonyl.3 In the past few years, great efforts have been
made to develop environmentally friendly processes toward
imine synthesis. The catalytic synthesis of imines from second-
ary amines4 and oxidative condensations of primary amines5
were also reported in the literature. Recently, transition metal-
catalyzed oxidative imine synthesis directly from alcohols and
amines, without any oxidative preparation of aldehydes, has
been highlighted as a highly atom economical transformation
that generates water as the sole byproduct. Since the seminal
work of Milstein,6 a wide range of metal complexes have been
used as catalysts in this coupling reaction including ruthenium,7
osmium,8 palladium,9 platinum,10 gold,11 copper12 etc.
1
confirmed by H, 13C, and ESI-MS analysis. After this initial
promising result, we studied the effect of base and solvent on the
reaction yield. Various bases were tested for the catalytic reac-
tion. Among them, KOH gave the highest yield of product 3a.
NaOH also showed catalytic activity for the reaction, but pro-
vided coupling products in only 60% yield (Table 1, entry 4).
Some strong bases, t-BuONa and t-BuOK (Table 1, entries 2–3),
gave high conversions of the starting materials but the product in
low yield. Others such as K2CO3 and triethylamine were less
effective, giving 3a in very low yield (Table 1, entries 5–7).
Increase in the amount of KOH did not have any appreciable
impact on the chemical yield (Table 1, entries 1, 8 and 9). In the
presence of 0.2 equiv of CsOH, good solubility in toluene, 87%
product was formed (Table 1, entry 15). Because reagent-grade
KOH is known to have transition metal contaminants, semi-
conductor-grade KOH, 99.99% pure based on trace metal analysis
(Alfa Aesar), was also examined (Table 1, entry 10). As seen in
Table 1, the use of semiconductor-grade KOH did not change
the product or yield versus the reagent-grade base. The screening
of a range of solvents showed that the toluene was the best
choice (Table 1, entries 1 and 14). Lowering the reaction temp-
erature to 90 °C still gave 91% of 3a under the same conditions
(Table 1, entry 14). Under argon atmosphere, no desired product
was observed (Table 1, entry 16).
To our knowledge, the direct condensation of primary amines
with primary alcohols without any transition metal complex for
Department of Chemistry, College of Chemistry and Chemical
Engineering, and the Key Laboratory for Chemical Biology of Fujian
Province, Xiamen University, Xiamen 361005, P.R. China.
E-mail: t12g21@xmu.edu.cn; Fax: +86-592-2185780;
Tel: +86-592-2185780
†Electronic supplementary information (ESI) available: Experimental
section, spectral data and other supplementary information. See DOI:
10.1039/c2gc35714c
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Table 1 Reaction conditions optimizationa
Table 2 Base-mediated aerobic oxidative imines preparation from
alcohols and aminesa
Entry
Base
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Dioxene
H2O
Toluene
Toluene
Toluene
110
110
110
110
110
110
110
110
110
110
66
101
100
90
90
90
92
56
18
60
5
t-BuONa
t-BuOK
NaOH
K2CO3
Cs2CO3
Et3N
KOH
KOH
KOH
KOH
KOH
KOH
KOH
CsOH
KOH
3
Trace
91
85
91
56
80
0
91
87
Trace
8c
9d
10e
11
12
13d
14
15f
16g
a Reaction conditions: benzyl alcohol (3.6 mmol) and aniline
(3.0 mmol), base (6.0 mmol), 2.5 mL toluene (reflux), open to air, 20 h.
b Yields were determined by 1H NMR using an internal standard
(anisole). c 3.6 mmol KOH was used. d 0.8 equiv. of KOH was used.
e Denotes use of semiconductor-grade KOH. f 0.2 equiv. of CsOH was
used. g In argon ambient.
With these optimized reaction conditions, a variety of sub-
strates were surveyed to explore the scope and limitations of the
reaction (Table 2). In all cases, the corresponding N-alkylation
products were detected in 2–10% yields by 1H NMR. Our KOH-
mediated system is effective for a wide combination of primary
amines and benzyl alcohols giving the corresponding imines in
good yields under aerobic atmosphere. The reaction of aromatic
amines with 1a afforded 3a–h in 80–97% yields. Similarly, the
reaction of aliphatic amines with 1a gave 3i–m in 85–96%
yields. The above results indicate that both aliphatic and aro-
matic amines work equally well with the reaction. Substituted
benzyl alcohols with 4-methoxy and 4-chloro groups also
reacted smoothly with aniline to afford products 3q and 3n in 97
and 87% yields. Similarly, treatment of benzyl alcohol with
4-methoxy and 4-chloro substituted anilines led to the formation
of products 3b and 3h in 97 and 80% yields, respectively. The
above results indicated that electron-withdrawing groups on the
phenyl ring substrates would significantly lower the yield. In
addition, this reaction was also compatible with bromo and
chloro substituents on the aromatic ring of benzyl alcohol and
aniline. Treatment of benzyl alcohol with 4-methyl and 2-methyl
substituted anilines afforded 3c and 3e in 95 and 87% yields,
respectively. Nevertheless, sterically bulkier 2,6-dimethyaniline
reacted with 2a, gave the corresponding imine in very low yield.
1-Phenylethanol and aliphatic primary alcohols were also exam-
ined. Unfortunately, no desired imine products were detected by
1H NMR.
a Reaction conditions: benzyl alcohol (3.6 mmol) and aniline
(3.0 mmol), KOH (3.6 mmol), 2.5 mL toluene, open to air, 90 °C, 20 h.
Yields were determined by 1H NMR using an internal standard
(anisole).
Scheme 1 Plausible reaction mechanism.
Because no ketone is included15 in our reaction mixtures,
another pathway must be responsible for the product formation,
as shown in Scheme 1.
The real role of the strong base is clear from a mechanistic
point of view; it is connected initially with the deprotonation of
The detailed reaction mechanism remains to be clarified.
Important recent studies have shown the use of alkali metal
bases for the oxidation of alcohols to the corresponding carbo-
nyls in excess acetone through an Oppenauer pathway.14
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400M spectrometers with CDCl3 as solvent and tetramethyl-
silane (TMS) as internal standard. Chemical shifts were reported
1
in units (ppm) by assigning TMS resonance in the H spectrum
as 0.00 ppm and CDCl3 resonance in the 13C spectrum as
77.0 ppm. All coupling constants (J values) were reported in
1
Hertz (Hz). Chemical shifts of common trace H NMR impuri-
ties (ppm): H2O: 1.56, CHCl3: 7.26. Column chromatography
was performed on basic alumina gel 200–300 mesh using pet-
roleum ether and ethyl acetate as the eluent. The CAS number of
the known compound was listed.
Scheme 2 Imines preparation from amines and alkali metal alkoxides.
Reaction conditions: (1) benzyl alcohol (3.6 mmol) and metal
(3.2 mmol), 5 mL toluene (reflux) in nitrogen atmosphere, 60 min, alkali
metal alkoxide was prepared; (2) aniline (3.0 mmol), open to air, 90 °C,
20 h. Yields were determined by 1H NMR using an internal standard
(anisole).
General procedure for the synthesis of 3a
A mixture of 3.0 mmol of aniline (1a), 3.6 mmol of benzyl
alcohol (2a), 3.6 mmol of potassium hydroxide in 2.5 mL
toluene was stirred under an atmosphere of air at 90 °C for 24 h.
The reaction mixture was then, without any workup, purified
directly by column chromatography on basic alumina gel (pet-
roleum ether (60–90 °C)–ethyl acetate–triethylamine 100 : 10 : 1)
to afford imine (3a) in 83% isolated yield.
the aryl-alcohol leading to the formation of the potassium aryl-
carbinoate intermediate; this intermediate could extrude a H−,
the Cannizzaro-like reaction16 under strong base or β-hydride
elimination in metal-catalyzed reactions,13,17 to form aryl-alde-
1
hyde. Benzaldehyde was also detected by H NMR in the reac-
tion solution. The same reaction using the in situ-prepared alkali
metal alkoxides (by deprotonation of benzyl alcohol with potass-
ium and sodium, Scheme 2) yield the expected product 3a in
good yields. This results also make the involvement of transition
metal traces in the base-promoted synthesis of imines
impossible.
Acknowledgements
We acknowledge financial support from the National Basic
Research Program of China (2012CB821600), the Chinese
National Natural Science Foundation (21173178, 20972130),
NFFTBS (J1030415), and TJAB-2009-023.
Subsequently, the formed H− could react with O2 to form
OH−. When the reaction was performed using aniline and benzyl
alcohol under nitrogen atmosphere, compound 3a was not
detected after 20 h, indicating that oxygen also has a significant
role in the catalytic reaction (Table 1, entry 2). The cross coup-
ling reaction of the amine with aldehyde generated affords the
product imine.
Notes and references
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Wang’s group reported the aerobic oxidation of a secondary
aryl-alcohol into its ketone promoted by NaH, and observed the
formation of hydrogen peroxide (NaOOH) in the reaction
system.18 After the imine synthesis completed in the KOH-
mediated reaction, the recovered insoluble powder was dissolved
in water and made acidic with HCl, H2O2 was not detected by
the potassium iodide/starch test. Moreover, only a 20% equival-
ent of CsOH can also promoted the imine synthesis (Table 1,
entry 15) and aerobic oxidation of sec-aromatic alcohols.19 The
above results proved that not OOH− but OH− was formed in the
KOH-mediated imine synthesis.
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Conclusions
In summary, we have established the first example of a base-
promoted green synthesis of highly desirable imines starting from
amines and alcohols. Both the use of air as an environment-
friendly oxidant and the elimination of transition metal catalyst
all constitute the charming characters of this procedure, render-
ing the experimental procedure very simple. Therefore, this pro-
tocol will have wide application for the construction of natural
products, biologically and therapeutically active compounds.
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Experimental
1
All reactions were carried out under air. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were measured on Bruker
2386 | Green Chem., 2012, 14, 2384–2387
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