Highly efficient iron phthalocyanine catalyzed oxidative synthesis of imines from alcohols and amines

Article abstract of DOI:10.1139/cjc-2012-0399

An efficient iron phthalocyanine catalyzed method was developed for direct oxidative coupling of alcohols with amines to afford corresponding imines. The present protocol is applicable to various substituted aromatic and aliphatic alcohols and amines. The reaction is believed to proceed via activation of alcohols by iron phthalocyanines through Lewis acid-base interaction to form aldehydes, which by nucleophilic attack of amines are converted into the corresponding imines.

Full text of DOI:10.1139/cjc-2012-0399

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Highly efficient iron phthalocyanine catalysed oxidative
synthesis of imines from alcohols and amines
Manju Bala, Praveen Kumar Verma, Neeraj Kumar, Upendra Sharma, and Bikram
Singh
Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology,
Palampur, Himachal Pradesh-176 061, INDIA
M. Bala, P. K. Verma, N. Kumar,1 U. Sharma, V. Kumar, B. Singh2
Natural Plant Products Division, CSIRꢀInstitute of Himalayan Bioresource Technology,
Palampur, H.P., 176 061, INDIA.
Tel.: 91ꢀ1894ꢀ230426; Fax: 91ꢀ1894ꢀ230433
1Corresponding author (eꢀ mail: neerajnpp@rediffmail.com).
2Corresponding author (eꢀ mail: bikram_npp@rediffmail.com).
†IHBT Communication No. 2362
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Abstract: An efficient iron phthalocyanine catalyzed method was developed for direct
oxidative coupling of alcohols with amines to afford corresponding imines. The present
protocol is applicable to various substituted aromatic and aliphatic alcohols and amines.
The reaction is believed to proceed via activation of alcohols by iron phthalocyanines
through Lewisꢀacid base interaction to form aldehydes, which by nucleophilic attack of
amines converted into the corresponding imines.
Keywords: iron phthalocyanine, imine synthesis, oxidative coupling, alcohols, amines.
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Introduction
Imines are versatile intermediates in organic synthesis involving pharmaceuticals,
agricultural chemicals, natural products, dyes and as elecrtophiles in many important
transformations including addition, condensation and cycloaddition.1 Traditionally,
imines were synthesized from the condensation of amines and aldehydes or ketones with
the azeotropic distillation of water.2 Imines have also been synthesized by selfꢀ
condensation of amines upon oxidation.3 In contrast to these methods, one pot approaches
for imine formation directly from oxidative coupling of alcohols with amines constitute
more environmentally benign approach. Different catalytic systems such as ruthenium
hydroxide supported on TiO2,4 manganese octahedral molecular sieves,5 palladium
catalyst,6 ruthenium pincer complex,7 POP type osmium complexes,8 Pt/TiO2
nanoparticles under UV irradiation,9 copper catalyst,10 and bimetallic Pt/Al2O3 catalyst11
have been reported for this type of reaction. However, use of costly metals, additives and
long reaction time limits their scope. Hence, the development of an efficient inexpensive
method is highly desirable.
In recent years, ironꢀbased complexes allowed for considerable inventions in
organometallic catalysis.12 Apart from the abundant availability, the low toxicity and
biomimetic preꢀcatalysts make iron an ideal metal for catalysis.13
In continuation of our work on metallophthalocyanines based catalysis14 recently,
we have successfully applied iron(II)phthalocyanine (FePc) for reduction of nitroarenes
to corresponding amines14d and thought to apply for the oxidative coupling of alcohols
with primary amines to form corresponding imines.
Results and discussion
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Initially, to optimize the best reaction conditions for the oxidative coupling of alcohols
and amines to form corresponding imines, the reaction of aniline with benzyl alcohol was
selected as model system (Table 1). Without catalyst very low yield was obtained (Table
1, entry 18). Among various tested iron catalysts best yield was recorded with FePc
(Table 1, entries 1ꢀ5). Although, FeCl3 also catalyze the reaction to good extent, yield of
the product was less as compared to FePc in each studied case (Table 1, entry 1; Table 2,
entry 7; Table 3, entry 6). Hence, FePc was selected as a catalyst of choice for the
reaction. Different bases such as K2CO3, Cs2CO3, DABCO and NaHCO3 provided very
low yield, while, moderate yield was observed with KOtBu (Table 1, entries 7ꢀ11). Best
results were achieved with NaOtBu (Table 1, entry 5). As expected without base desired
product was not observed (Table 1, entry 6). Reaction conditions were further optimized
by changing the reaction media. Reaction was not preceded in case of water, DMSO and
PEGꢀ400 (Table 1, entries 13, 15 and 17). In case of ethanol and DMF low yield of
desired product was recorded (Table 1, entries 14 and 16). Good yield was obtained in
1,4ꢀdioxane but best results were observed in toluene (93%) (Table 1, entries 12 and 5).
After optimizing the best reaction conditions, various combinations of alcohols and
amines were examined to form the corresponding imines (Table 2ꢀ3). The reaction of
benzyl alcohol with aniline resulted in high yield of corresponding imine (93%, Table 2,
entry 1). The halide substituted amines were successfully coupled with benzyl alcohol to
form corresponding imines without any dehalogenation (Table 2, entries 2ꢀ4). Excellent
yield was obtained with pꢀbromoaniline and pꢀflouroaniline whereas very low yield was
observed with mꢀbromoanilne (Table 2, entries 2ꢀ4). pꢀNitroaniline and tetrahydroamino
naphthalene afforded corresponding imine in very low yield even after 24 h (Table 2,
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entries 5 and 7). Moderate yield of imine was observed in case of 2,3ꢀdimethylaniline
(Table 2, entry 6), which may be due to the steric effect. Also, yield was not affected
much on increasing the duration of reaction up to 24 h (Table 2, entry 6). Good to
excellent yields were observed for various benzyl and phenylethyl amines (Table 2,
entries 8ꢀ12).
The scope of catalytic method was further explored for various substituted alcohols
(Table 3). Excellent yields were obtained in case of methoxy, ethoxy and bromo
substituted benzyl alcohols (Table 3, entries 1ꢀ3). The present protocol also successfully
catalyzes the oxidative coupling of aliphatic alcohols with amines to form corresponding
imines, which is one of the challenging tasks for chemists. The coupling of phenyl propyl
alcohol with aniline afforded imine in excellent yield, whereas, moderate yield was
observed in case of phenyl ethyl alcohol (Table 3, entries 4 and 5). Isoamyl alcohol also
afforded corresponding imine in moderate yield (Table 3, entry 6).
In addition to the oxidative coupling of alcohols with amines the present catalytic
system was also applicable to the self coupling of benzyl amine to form corresponding
imine. Also, no base was required for the self coupling reaction; FePc alone was able to
catalyse the reaction, as high yield of imine product was observed without using base
(Scheme 1).
The present catalytic system also efficiently catalysed the oxidation of benzyl alcohol
to benzaldehyde under the same reaction conditions (Scheme 2).
Although, the exact role of FePc was not clear, however, based on the fact that
transition metal phthalocyanines act as Lewis acids14b,14c we propose that, Lewis acidꢀ
base interaction between FePc and oxygen of alcohol promoted the NaOtBu mediated
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oxidation of alcohols to corresponding aldehydes, which undergo condensation with
amines to form imines (Fig. 1). This is supported by the fact that in the presence of
triethylamine (1 equiv.), no product was observed due to strong Lewis acidꢀbase
interaction of triethylamine with FePc (Scheme 3).
Conclusions
The use of abundantly available and low toxic iron based catalyst is an attractive catalytic
alternative to other costly and toxic transition metals. In present study, an efficient iron
phthalocyanine catalyzed method has been developed for the oxidative coupling of
alcohols with amines to form corresponding imines. Present catalytic system was also
able to catalyze the self coupling of benzyl amine to corresponding imine and oxidation
of benzyl alcohol to benzaldehyde.
Experimental
Materials and Instrumentation
Metal salts used were purchased from Merck, Germany. Iron phthalocyanine was
purchased from SigmaꢀAldrich, USA. Silica gel (60ꢀ120 mesh) used for column
chromatography was purchased from Sisco Research Laboratories Pvt. Ltd. India and all
other chemicals were purchased from Spectrochem, India,; Merck, Germany, and Sigmaꢀ
Aldrich, USA and were used without further purification. NMR spectra were recorded on
a Bruker Avanceꢀ300 spectrometer. The GCꢀMS analysis was carried out on a Shimadzu
(QP 2010) series Gas ChromatogramꢀMass Spectrometer (Tokyo, Japan), AOCꢀ20i autoꢀ
sampler coupled, and a DBꢀ5MS capillary column, (30 m x 0.25 mm i.d., 0.25ꢁm). The
initial temperature of column was 70 °C held for 4 min. and was programmed to 230 °C
at 4°C/min., then held for 15 min. at 230 °C; the sample injection volume was 2 ꢁl in GC
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grade dichloromethane. Helium was used as carrier gas at a flow rate of 1.1 ml minꢀ1 on
split mode (1: 50).
General procedure for the oxidative coupling of alcohols with amines
To a stirred suspension of FePc (1 mol%) and NaOtBu (2 equiv.) in toluene (3 mL) were
added alcohol (1.0 mmol), amine (1.0 mmol) at room temperature and then the
o
temperature was raised to 80 C for 12 h under N2 atmosphere. On completion of the
reaction (as monitored by TLC), reaction mixture was filtered and passed through
anhydrous Na2SO4 and dried under vacuum. The crude product was analyzed by GCꢀMS
or purified by column chromatography over silicaꢀgel (60ꢀ120 mesh) with appropriate
mixture of nꢀhexane and ethyl acetate. The GCꢀMS yields of products were calculated on
the basis of amine reactants. The following compounds were characterized on the basis of
NMR and GCꢀMS data given below:
1
NꢀBenzylideneaniline (Table 2, entry 1): Yellowish powder, Yield = 87%; H NMR
(CDCl3, 300 MHz) δ = 7.21ꢀ7.49 (m, 7H), 7.74ꢀ7.83 (m, 3H), 8.18 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ = 128.1, 129.6, 130.0, 130.2, 133.0, 133.8, 144.3; GCꢀMS (EI): m/z
181 [M]+, 152, 104, 89, 77, 63, 51.
1
NꢀBenzylideneꢀ4ꢀfluoroaniline (Table 2, entry 2): Colourless oil, Yield = 83%; H NMR
(CDCl3, 300 MHz) δ = 7.07ꢀ7.13 (m, 2H), 7.20ꢀ7.28 (m, 2H), 7.49ꢀ7.58 (m, 3H), 7.90ꢀ
13
7.93 (m, 2H), 8.46 (s, 1H); C NMR (CDCl3, 75 MHz) δ = 116.1, 116.4, 122.6, 122.7,
129.1, 131.8, 136.4, 148.4, 160.5; GCꢀMS (EI): m/z 199 [M]+, 151, 122, 95, 75, 63, 51.
Acknowledgments
Authors are grateful to the Director of the institute for providing necessary facility and
encouragement. P.K.V. and U.S. are also thankful to CSIR for fellowship.
7

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Table 1. Optimization of reaction conditions for imine
synthesis from benzyl alcohol and aniline.a
NH2
OH
+
Catalyst (1 mol%), Solvent, N2
Base (2 equiv.), 80 oC, 12 h
N
Entry Catalyst
Base
Solvent
Yield (%)b
1
2
3
FeCl3
Fe2O3
FeSO4
NaOtBu Toluene
NaOtBu Toluene
NaOtBu Toluene
72
54
60
4
Iron metal NaOtBu Toluene
53
5
6
7
8
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
ꢀ
NaOtBu Toluene
93
ꢀ
Toluene
Toluene
Toluene
Toluene
No Reaction
K2CO3
KOtBu
Cs2CO3
19
55
16
26
16
9
10
11
12
13
14
15
16
17
18
DABCO Toluene
NaHCO3 Toluene
NaOtBu 1,4 Dioxane 77
NaOtBu H2O
No Reaction
39
No Reaction
57
No Reaction
35
NaOtBu EtOH
NaOtBu DMSO
NaOtBu DMF
NaOtBu PEGꢀ400
NaOtBu Toluene
a Reaction conditions: aniline (1 mmol), benzyl alcohol (1 mmol), FePc
o
(1 mol%), base (2 equiv.), toluene (3 mL), 80 C, 12 h, N2.
b Yield was calculated on the basis of GCꢀMS analysis.
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Table 2. One pot imine synthesis from benzyl alcohol
with various amines.a
R1
FePc (1 mol%), Toluene, N2
NaOtBu (2 equiv.), 80 oC, 12 h
OH
+
N
R1 NH2
Entry Amine
Product
Yield (%)b
93 (87)
NH2
1
N
F
NH2
2
3
4
89 (83)
22
N
F
NH2
N
Br
Br
Br
NH2
NH2
93
N
Br
NO2
5
6
7
18c
N
O2N
NH2
CH3
H3C
H3C
H3C
60
69c
N
13
27d
11d,e
N
NH2
NH2
N
8
98
94
98
O
O
O
O
NH2
N
9
NH2
N
10
NH2
N
11
76
99
H3CO
HO
H3CO
HO
N
NH 2
12
a
Reaction conditions: amines (1 mmol), benzyl alcohol (1 mmol),
o
FePc (1 mol%), NaOtBu (2 equiv.), toluene (3 mL), 80 C, 12 h, N2.
b Yield was calculated on the basis of GCꢀMS analysis. Isolated yield
are given in parenthesis.
c Reaction time 24 h.
d 1.5 equiv. of alcohol was used.
e Reaction was carried out with FeCl3.
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Table 3. One pot imine synthesis from various
alcohols with aniline.a
NH2
FePc (1 mol%), Toluene, N2
OH
+
R1
NaOtBu (2 equiv.), 80 oC, 12 h
N
R1
Entry Alcohol
Product
Yield (%)b
OH
N
1
94
98
OCH3
OCH3
OH
N
OC2H5
N
2
OC2H5
OH
Br
3
4
5
91
56
Br
OH
N
OH
93
N
CH3
CH3
CH3
56
5c,d
N
6
HO
CH3
a Reaction conditions: aniline (1 mmol), alcohols (1 mmol), FePc
(1 mol%), NaOtBu (2 equiv.), toluene (3 mL), 80 oC, 12 h, N2.
b Yield was calculated on the basis of GCꢀMS analysis.
c Reaction was carried out with FeCl3.
d Reaction time 24 h.
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Fig. 1. Proposed pathway for oxidative coupling of alcohols with amines to form
imines.
HOtBu
Na+
OtBuꢀ
H
R1
O
R1CH2ONa
HOtBu
H2 + NaOtBu
N
N
N
R1CHO
N
N
Fe
N
R2NH2
N
H2O
R1
N
R2
N
14

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Scheme 1. Self coupling reaction of benzyl amine to form corresponding imine.
N
FePc (1 mol%), Toluene, N2
NaOtBu (2 equiv.), 80 oC, 24 h
NH2
H2N
GC-MS Yield = 70 %
N
+
FePc (1 mol%), Toluene, N2
No Base, 80 oC, 24 h
GC-MS Yield = 90 %
Scheme 2. Oxidation of benzyl alcohol to benzaldehyde.
OH
FePc (1 mol%), NaOtBu (2 equiv.)
O
Toluene, 80 oC, 12 h
1 mmol
GCꢀMS Yield = 92 %
Scheme 3. Reaction of benzyl alcohol with aniline in the presence of triethylamine.
NH2
OH
FePc (1 mol%), Et3N (1 equiv.)
+
No Reaction
Toluene, 80 oC, 12 h
1 mmol
1 mmol
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Graphical abstract:
Highly efficient iron phthalocyanine catalysed oxidative synthesis of
imines from alcohols and amines
Manju Bala, Praveen Kumar Verma, Neeraj Kumar, Upendra Sharma, and
Bikram Singh
N
N
N
N
N
R1
R1-NH2
R2-CH2OH
Fe
N
+
N
N
R2
N
FePc (1 mol%)
t-BuONa (2 equiv.), Toluene
An efficient iron phthalocyanine catalyzed method was developed for direct oxidative
coupling of alcohols with amines to afford corresponding imines. The present
protocol is applicable to various substituted aromatic and aliphatic alcohols and
amines.