Copper-catalyzed aerobic oxidation of amines to imines under neat conditions with low catalyst loading

Article abstract of DOI:10.1002/adsc.201100100

The copper (I)-catalyzed direct synthesis of imines from amines under mild aerobic conditions is described. The method is applicable for the synthesis of various imines from corresponding amines such as benzylic, aliphatic, cyclic secondary, heteroaromatic species and the oxidative condensation of benzylamines with anilines extends the scope of the CuCl catalytic system. Noteworthy, solvent-free procedure, air as a benign oxidant, and the cheap and easy availability of the catalyst are the vital advantages of the method. Copyright

Full text of DOI:10.1002/adsc.201100100

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DOI: 10.1002/adsc.201100100
Copper-Catalyzed Aerobic Oxidation of Amines to Imines under
Neat Conditions with Low Catalyst Loading
Rajendra D. Patila and Subbarayappa Adimurthya,*
a
Analytical Science Division, Central Salt & Marine Chemicals Research Institute (CSIR), G.B. Marg, Bhavnagar –
364002, India
Fax : (+91)-278-256-7562; e-mail: sadimurthy@yahoo.com
Received: February 9, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100100.
Abstract: The copper (I)-catalyzed direct synthesis
of imines from amines under mild aerobic condi-
tions is described. The method is applicable for the
synthesis of various imines from corresponding
amines such as benzylic, aliphatic, cyclic secondary,
heteroaromatic species and the oxidative condensa-
tion of benzylamines with anilines extends the
scope of the CuCl catalytic system. Noteworthy, sol-
vent-free procedure, air as a benign oxidant, and
the cheap and easy availability of the catalyst are
the vital advantages of the method.
benzylamines under relatively mild and neat condi-
tions without producing waste is highly desirable eco-
nomically and environmentally.
We recently reported a selective oxidation of vari-
ous alcohols to the corresponding carbonyl com-
pounds[6] with a mild and selective oxidizing agent
(BrOH) generated in-situ from the bromide/bromate
couple in aqueous acidic medium [Eq. (1)].[7]
Keywords: copper; homogeneous catalysis; imines;
oxidation; synthetic methods
When the same species (BrOH) is used for the oxi-
dation of benzylamine to the imine, lower yields were
obtained under aqueous conditions.[8] Based on these
results we hypothesized that a related halogen species
under non-aqueous conditions may possibly provide
Imines are important intermediates in the synthesis of high selectivity for this transformation. To our delight,
various biologically active nitrogen-containing hetero- we found that copper catalysts function well in this
cyclic compounds and industrial synthetic processes.[1] context. Herein, we demonstrate a novel approach to
Significant progress has been made in recent years for the direct synthesis of imines from readily available
the synthesis of imines, including the direct synthesis benzylamines, under mild conditions using an inex-
of imines from amines and alcohols in the presence of pensive and commercially available copper catalyst
catalyst,[2] self-condensation of primary amines with and air as an oxidant [Eq. (2)]. To the best of our
oxidant[3] and oxidation of secondary amines.[4] Most
of these reactions were performed under solvent con-
ditions. However, no attempts were made for the syn-
thesis of imines by the direct oxidation of primary
amines to the corresponding imines under neat condi-
tions, probably due to the rapid dehydrogenation of
imines to nitriles in solvent media.[5]
knowledge this is the first convenient catalytic process
Notably, most of the applications are based on com- ever reported for efficient syntheses of imines from
plexes of precious metals such as palladium, rutheni- benzylamines using air as the oxidant under neat con-
um, gold and vanadium. The limited availability of ditions with low catalyst loadings.
these metals and their high price makes it highly de-
During our studies we examined the synthesis of
sirable to search for more economical and environ- imine (2a) using the copper-catalyzed aerobic oxida-
mental-friendly alternatives. Thus, the selective, cata- tive imination of benzylamine under mild and sol-
lytic synthesis of benzylimines directly from primary vent-free conditions (Table 1). Employment of
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Rajendra D. Patil and Subbarayappa Adimurthy
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Table 1. Optimization of the conditions for the copper-cata-
lyzed oxidation of 1.[a]
tries 9–18). After extensive screening of various
copper catalysts, it was discovered that 0.5 mol% cop-
per(I) chloride at 1008C under air were the optimized
reaction conditions for the present investigation
(Table 1, entry 2).
Under these optimized conditions, various imines
were produced from their corresponding benzyla-
mines. The results in Table 2 demonstrate that this re-
action has a high degree of functional group toler-
ance. Both electron-rich (para, meta, and ortho substi-
tuted) and electron-deficient substrates were well tol-
erated and produced moderate to excellent yields. It
is noteworthy that halo-substituted benzylamines per-
formed well, leading to halo-substituted imine com-
pounds (Table 2, entries 5–10), which could be used
for further transformations along with the imine func-
tionality. Furthermore, it should be noted that with
the use of a more than stoichiometric amount of gold
catalyst (2.5 equiv. referred to substrate) only a 7%
yield of 2h was reported.[9] However, under our condi-
tions using copper(I) chloride as catalyst (0.005 equiv.
referred to substrate) the same product 2h could be
obtained in 90% yield (Table 2, entry 8). Further-
more, we admit that the isolated products of Table 2
indicate the presence of some aldehyde that could be
due to hydrolysis of the imine during work-up.[5e] This
is also evidenced from Table 1, when the crude mix-
ture was analyzed by GC-MS, it showed only imine
with no evidence for the formation of aldehyde.
Entry Catalyst [mol%] Conversion Yield
Selecivity
[%]
[%]
[%][b]
1
2
3
4
5
6
7
8
9
10
CuCl [0.2]
CuCl [0.5]
CuCl [1.0]
CuCl [0.5][c]
CuCl [0.5][c]
CuCl [0.5][d]
CuCl [0.5][d]
no catalyst
CuCl2 [0.5]
53
100
100
–
68
40
91
–
52
>99
>99
–
68
34
85
–
98
100
100
–
100
85
93
–
100
27
77
77
27
CuACHTUNGTRENNUNG(ClO4)2·5H2O 100
[0.5]
11
12
13
14
15
CuI [0.5]
CuBr [0.5]
CuBr2 [0.5]
CuF2 [0.5]
100
78
88
89
73
83
22
78
89
94
94
100
80
22
Cu
[0.5]
Cu(NO3)2·3H2O 81
ACHTUNGTRENNUNG(OAc)2·H2O 97
16
G
72
89
[0.5]
17
18
CuO [0.5]
CuSO4·5H2O
[0.5]
31
48
31
47
100
98
19[e] CuCl [0.5]
92
23
83
23
89
100
The successful transformation of benzylamines into
the corresponding imines under neat conditions with
20[f]
CuCl [0.5]
[a]
Reaction conditions: benzylamine 1 (9.3 mmol), catalyst, such a low catalyst loading (0.5 mol%) prompted us
T=1008C, open air atmosphere; time=18 h ( unless oth-
erwise stated).
Yield based on GC area%.
Reaction carried out at room temperature (entry 4) and
at 608C (entry 5).
Reactions carried out in toluene (entry 6) and THF
(entry 7) as solvents.
Reaction performed under an oxygen atmosphere (bal-
loon).
Reaction performed under an argon atmosphere.
to investigate the generality of this method for the
synthesis of other imines with various amine sub-
strates (Table 3). To our delight, we found this trans-
formation to be very general for a wide range of
amines such as dibenzylamine (Table 3, entry 1),
cyclic secondary amines (Table 3, entries 2 and 3), a
heteroaromatic amine (Table 3, entry 4) and an ali-
phatic amine (Table 3, entry 5) as substrates and pro-
duced the corresponding imines in good yields. In the
case of pyridin-2-ylmethanamine, 60% of picolina-
mide also obtained in addition to the desired imine
[b]
[c]
[d]
[e]
[f]
0.5 mol% of copper(I) chloride as a catalyst under (Table 3, entry 4) which is apparent according to the
neat conditions is the key step for the high efficiency literature.[3c] However, the conversion products of
of this transformation (Table 1, entries 1 and 2). No cyclic amines[10] (Table 3, entries 2 and 3) and n-hexyl-
reduction of reaction time was observed when catalyst amine (Table 3, entry 5) could be obtained in good
loading was increased to 1 mol% (Table 1, entry 3). yields under the present reaction conditions but are
Also no reaction occurred at room temperature, how- reported to be unaffected even with metal organic
ever at 608C, 68% conversion was observed (Table 1, framework solid catalytst.[3c]
entries 4 and 5). Furthermore, no improvements were
By using the newly established protocol, we at-
observed when the reaction was carried out in toluene tempted the synthesis of unsymmetrically substituted
and THF (Table 1, entries 6 and 7). The reaction does imines. Thus, syntheses of unsymmetrical imines 5
not proceed without the catalyst (Table 1, entry 8). were carried out by reacting benzylamine 1a with dif-
Attempts were made to use copper halides and other ferent anilines 4a–e, 3-methyl-2-aminopyridine 4f and
copper catalysts but they were not efficient to achieve the aliphatic amine 4g under neat conditions
the required conversion and selectivity (Table 1, en- (Table 4). Anilines bearing electron-releasing and
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Adv. Synth. Catal. 2011, 353, 1695 – 1700

Copper-Catalyzed Aerobic Oxidation of Amines to Imines under Neat Conditions
Table 2. Copper-catalyzed aerobic oxidation of benzylamines to imines.[a]
[a]
Reaction conditions: 1 (10 mmol), CuCl (0.05 mmol), T=1008C, open air atmosphere.
[b]
Isolated products.
Selectivity determined by H NMR.
[c]
[d]
1
Rest of starting benzylamine was recovered.
electron-withdrawing substituents provided good is the formation of complex A with oxidative addtion
yields of imines (Table 4, entries 1–4). The reaction of of copper to the amine.[11,12] Further oxidation of com-
benzylamine with the strong electron-withdrawing 3- plex A, provided methanimine B. Reaction of metha-
nitroaniline, however, produced only the symmetrical nimine B with another amine leads to the final imine
imine 2a (Table 4, entry 5). A similar inclination was product with liberation of ammonia (path 1). On the
observed with a heteroaromatic amine substrate other hand the presence of water partly hydrolyses
(Table 4, entry 6). This is due to the competitive nue- the methanimine B to aldehyde (path 2). The final
leophilicity of amines. Thus, 3-nitroaniline and 3- step (path 2) is the condensation of the aldehyde with
methyl-2-aminopyridine were recovered as such.
the amine leading to the formation of the imine. Par-
Although we have not isolated the intermediates ticularly, in unsymmetrical imine syntheses (Table 4),
(A and B), we propose a reaction pathway as outlined the nucleophilicity of the amines plays a major role
in Scheme 1. In the proposed mechanism the first step and leads to a mixture of imines 5 and 2. However, n-
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Rajendra D. Patil and Subbarayappa Adimurthy
Table 3. Copper-catalyzed aerobic oxidation of other amines to imines.[a]
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[a]
Reactions conditions: 1 (10 mmol), CuCl (0.05 mmol), T=1008C, open air at-
mosphere.
Yields based on H NMR of crude product unless otherwise stated.
Isolated yield.
[b]
[c]
1
Table 4. Synthesis of unsymmetrical imines.<W=3
[a]
Conversions based on benzylamine 1a (GC area%).
Isolated yield unless stated.
GC yields referred to 1a [4e and 4f remained unreacted].
[b]
[c]
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Copper-Catalyzed Aerobic Oxidation of Amines to Imines under Neat Conditions
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Experimental Section
Synthesis of Benzylimine (2a)
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