Synthesis of prochiral imines from aromatic ketones using magnesium perchlorate as catalytic promotor

Article abstract of DOI:10.1080/00397911.2012.681828

We report the synthesis of new prochiral imines by the reaction of nonsymmetric benzophenone derivates, bencylamines, and anilines in good yields. All the products were characterized by ¹H and ¹³C NMR as an isomeric E/Z mixture. Also

Full text of DOI:10.1080/00397911.2012.681828

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Synthesis of Prochiral Imines from
Aromatic Ketones Using Magnesium
Perchlorate as Catalytic Promotor
Manuel Amézquita-Valencia a , Gloria Alejandra Suárez-Ortiz a
Armando Cabrera a
&
a Instituto de Química, Universidad Nacional Autónoma de México,
Ciudad Universitaria, Circuito Exterior, Coyoacán, México
Accepted author version posted online: 10 Jan 2013.Version of
record first published: 05 Apr 2013.
To cite this article: Manuel Amézquita-Valencia , Gloria Alejandra Suárez-Ortiz & Armando Cabrera
(2013): Synthesis of Prochiral Imines from Aromatic Ketones Using Magnesium Perchlorate as Catalytic
Promotor, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 43:14, 1947-1954
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Synthetic Communications1, 43: 1947–1954, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.681828
SYNTHESIS OF PROCHIRAL IMINES FROM AROMATIC
KETONES USING MAGNESIUM PERCHLORATE AS
CATALYTIC PROMOTOR
´
Manuel Amezquita-Valencia, Gloria Alejandra Suarez-Ortiz,
and Armando Cabrera
´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico,
Ciudad Universitaria, Circuito Exterior, Coyoacan, Mexico
´
´
´
´
GRAPHICAL ABSTRACT
Abstract We report the synthesis of new prochiral imines by the reaction of nonsymmetric
benzophenone derivates, bencylamines, and anilines in good yields. All the products were
characterized by 1H and 13C NMR as an isomeric E=Z mixture. Also, the molecular struc-
tures for five derivatives determined by single-crystal x-ray experiments are presented.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Benzophenone; catalysis; magnesium perchlorate; prochiral imines; synthesis
of imines
INTRODUCTION
Nitrogen atoms are found in most natural products, in molecules with
biological activity[1,2] pharmaceutical[1–6] and agrochemical compounds. In this con-
text, imines and their derivatives are significant intermediaries in the synthesis of
lipoxygenase inhibitors,[2] anti-inflammatory and anticancerigen agents, as well as
synthetic a,b-amino acids not present in nature.[7–9] Likewise, prochiral imines are
mediators to obtain compounds with biological activity, and therefore the develop-
ment of highly efficient methodologies for the synthesis of molecules containing these
functional groups is considered of major relevance. In the literature it is possible to
find several methods for obtaining imines, based on the use of different precursors.
Received March 7, 2012.
Address correspondence to Armando Cabrera, Instituto de Quımica, Universidad Nacional
´
Autonoma de Mexico, Ciudad Universitaria, Circuito Exterior, Coyoacan 04510, Mexico. E-mail:
´
arcaor1@unam.mx
´
´
´
1947

´
´
M. AMEZQUITA-VALENCIA, G. A. SUAREZ-ORTIZ, AND A. CABRERA
1948
Thus, nonprochiral imines can be obtained from aldehydes,[10] symmetric ketones,[11]
and alcohols,[14] and meanwhile prochiral imines can be synthetized from nonsym-
metric ketones.[12,13] On the other hand, the conventional methods to obtain imines
are based on refluxing reactions with Dean–Stark apparatus or in the presence of
molecular sieves as water-removing agents. These systems require time-consuming
reactions as well as large quantities of aromatic solvents. Hence, alternative meth-
odologies have been employed such as the use of microwave[11] and ultrasound,[15]
systems that involve specific equipment and give poor yields when working with
ketones[16] because of their low reactivity compared with aldehydes.[16] Noteworthy
is the use of Lewis acids in this reactions, such as ZnCl2,[17] TiCl4,[18] alumina,[19]
silica, K-10,[20] Ti(OR)4, and Mg(SO4)2, which have allowed the use of smaller quan-
tities of solvents and increased reaction yields.
In this communication, we report a highly efficient methodology for the prep-
aration of prochiral imines from nonsymmetric aromatic ketones using magnesium
perchlorate as catalytic promoter, by the modification of a previously reported sys-
tem for the formation of aldoimines,[21] which do not have the synthetic potential of
nonsymmetric ketoimines.[22,23]
RESULTS AND DISCUSSION
The first approach to using the Lewis acid magnesium perchlorate in the
general catalytic transformation of nonsymmetric aromatic ketones to imines was
the synthesis of N-[(4-chlorophenyl)(phenyl)methylene]benzylamine 1b. With this
system, we were able to find the best reaction conditions through the variation of
the catalyst load, temperature, and reaction time (Table 1).
Hence, poor reaction yields were observed upon carrying out the reactions at
room temperature with different catalyst amounts (entries 1, 3, 6, 9). However, tem-
perature increases until reflux favored substrate conversion (entries 5, 8, 13). A simi-
lar phenomenon was observed when increasing the catalyst load 1–10% (entries 5, 8,
11, 12, 14). We found an optimum catalyst amount of 3%, observing that conversion
was not altered after a 5% of Mg(ClO4)2 (entries 8, 11, 14). The addition of a desic-
cant agent, such as MgSO4 or Na2SO4, led to the best results (entries 5, 8, 11, 12, 14).
In Table 2 the effect of the solvent on the behavior of the reaction in obtaining imine
1b was observed, and the best yields were found when using dichloroethane (DCE).
When dichloromethane (DCM), tetrahydrofuran (THF), EtOH, and MeCN were
used, conversion decreased because of the coordinating nature of the solvent.[21]
After finding the best conditions for the new catalytic system, the following
protocol was applied for the synthesis of a series of unreported prochiral imines,
using prochiral aromatic ketones as precursors (Scheme 1). Results are shown in
Table 3.
A wide range of aniline and benzylamine derivatives were employed, obtaining
good conversions >85% in most cases (Table 3). It was observed that the method is
tolerant of electron-donating and electron-withdrawing substituents. Also, the pres-
ence of para and meta substituted anilines (entries 9–20) did not affect the observed
reactivity; however, when methoxy group is para substituted we observed lower
yields (entries 14 and 15), and the use of ortho substituted anilines (entries 21 and
22) decreased the conversion. This behavior can be attributed to the greater steric

SYNTHESIS OF PROCHIRAL IMINES
1949
Table 1. Synthesis of imine 1b under various conditions
Entrya
Time (h)
Mg(ClO4)2 (% mol)
Temp. (ꢀC)
Yieldb (%)
1
2
12
12
12
12
12
12
12
12
15
15
15
24
24
24
24
1
1
rt
50
28
50c
33
3
2
rt
50
4
2
38
5
2
Reflux
rt
50
75c
38
6
3
7
3
55
8
3
Reflux
rt
50
86c
40
9
5
10
11
12
13
14
15
5
52
5
Reflux
Reflux
Reflux
Reflux
Reflux
85c
86c
65
6
6
10
0
85c
0
a5 mL of dry DCE.
bYields determined by GC.
cReaction with Na2SO4 or MgSO4.
effect of the substituent at the ortho position of the aromatic ring. A drastic decrease
in the conversion rate was observed in the systems containing aniline as a precursor
(entries 1–4).
On the other hand, the formation of imines from benzylamine derivatives
resulted in good conversions despite the presence of substituents in para and meta
positions in the aromatic ring (entries 23–45), as is evident for compounds 1g, 2i,
3k, 3l, 3m, and 1n, whereas the substrate 1j substituted with methoxy group again
gave a lower yield. Interestingly, the use of benzylamine as precursor generated good
conversion yields (entries 5–8), unlike aniline, which could be attributable to the
Table 2. Effect of different solvents in the synthesis of 1b
Entrya,b
Solvent
Yieldc(%)
1
2
3
4
THF
EtOH
MeCN
DCE
15
5
60
86
aReaction with Na2SO4 or MgSO4.
b5 mL of solvent.
cYields determined by GC.

´
´
M. AMEZQUITA-VALENCIA, G. A. SUAREZ-ORTIZ, AND A. CABRERA
1950
Scheme 1. General reaction for imine synthesis.
enhanced nucleophilic character of the nitrogen atom as a result of the higher
basicity in the amine group.
1
All compounds were characterized by mass spectrometry and H, and 13C
NMR (see the experimental section). The ratio between structural isomers of the
1
synthesized imines could be established through H NMR experiments (Table 3),
where the E isomer was the dominant configuration for most of the cases, except
compounds 4d, 1i, 1l, and 2l, where the Z isomer was the most abundant configur-
ation. These results were confirmed by nuclear overhauser spectroscopy (NOESY)
bidimensional experiments. Crystals of compounds 2c, 4c, 4d, 1k, and 2n suitable
for x-ray analysis were recrystallized from hexane solutions, and the respective
molecular structures confirmed obtained imines. Supplementary material crystallo-
graphic data for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre (CCDC Nos. 837357, 837358, 837359, 837360,
837364). In the case of compounds 4c and 4d, only isomer E was found in the mol-
ecular structure, whereas 2c, 1k, and 2n were found in a mixture of E=Z isomers with
3%, 12% and 5% of residual disorder, respectively (Fig. 1). For these compounds, all
bond lengths, angles, and dihedral angles are in agreement with similar systems
reported previously.[24,25] However, 1k has a dihedral angle between p-CF3C6H4
and p-ClC6H4 (15.01 ꢀ) because of the presence of the methylene group. In this con-
text, a weak hydrogen bond was found in the crystalline packing of compound 2c
between a hydrogen atom of an aromatic ring and the fluorine atom attached to
˚
the adjacent aromatic system (CH ꢁ ꢁ ꢁ F ¼ 2.61 A).
The scope of the reaction was further widened using aryl, alkyl, cyclo, hetero-
cyclic, and ferrocenyl ketones with different benzylamine or aniline derivatives. It
was found that cyclo1o–3o and alkyl–aryl 1p–2p ketones gave the corresponding imi-
nes in good yields, although the presence of an alkyl chain in the aromatic ring
reduces the stability of 1q. On the other hand, a heterocyclic substrate such as com-
pound 1s afforded the corresponding products in moderate yields. These results indi-
cate that the reaction can be carried out effectively with a diverse group of ketones
with good yields (Table 4.)
In conclusion, prochiral imines were synthesized from nonsymmetric aromatic
ketones and amine derivatives by the use of aniline and benzylamine as nucleophiles,
in the presence of Mg(ClO4)2 as catalytic promotor. Perchlorates salts are potentially
explosive when used in presence of combustible substances at high temperatures.[26]
.
However, some perchlorate salts have high thermal stability,[27] and exposure to
nominal levels of perchlorate does not adversely affect health and safety.[28] It was
possible to determine a high reaction tolerance to a wide variety of electron-donating
and electron-withdrawing substituents in the meta and para positions of the aromatic
rings in the amine precursors. Also, the use of benzylamine derivatives resulted in an

SYNTHESIS OF PROCHIRAL IMINES
1951
Table 3. Synthesis of imines via the condensation of prochiral benzophenone derivatives with amines cat-
[27]
alyzed by Mg(ClO4)2
Entry
R1
Amines
Product
Yieldsa (%)
E=Zb ratio
1
2
Cl
F
PhNH2
PhNH2
PhNH2
PhNH2
1a
2a
3a
4a
1b
2b
3b
4b
1c
2c
3c
4c
1d
2d
3d
4d
1e
2e
3e
4e
1f
4
5
—
—
3
Me
N(Me)2
Cl
5
—
—
4
10
87
86
84
95
86
86
84
93
83
60
20
94
91
82
81
91
72
70
80
78
63
69
70
73
75
81
76
41
73
94
93
89
88
87
95
86
75
89
79
94
86
5
PhCH2NH2
PhCH2NH2
62=38
63=37
62=38
70=30
54=46
56=44
62=38
71=29
55=45
55=45
55=45
28=72
62=38
54=46
63=37
75=25
73=27
61=39
63=37
63=37
52=48
62=38
53=47
53=47
49=51
63=37
52=48
59=41
52=48
64=36
52=48
51=49
41=59
49=51
53=47
58=42
54=46
55=45
53=47
56=44
55=45
6
F
7
Me
N(Me)2
Cl
PhCH2NH2
PhCH2NH2
8
9
4-Me-C6H4NH2
4-Me-C6H4NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
F
Me
N(Me)2
Cl
4-Me-C6H4NH2
4-Me-C6H4NH2
4-MeO-C6H4NH2
4-MeO-C6H4NH2
4-MeO-C6H4NH2
4-MeO-C6H4NH2
3-Cl-C6H4NH2
F
Me
N(Me)2
Cl
F
3-Cl-C6H4NH2
3-Cl-C6H4NH2
3-Cl-C6H4NH2
Me
N(Me)2
Cl
2-MeO-C6H4NH2
2-MeO-C6H4NH2
4-Me-C6H4CH2NH2
4-Me-C6H4CH2NH2
4-Me-C6H4CH2NH2
4-Cl-C6H4CH2NH2
4-Cl-C6H4CH2NH2
4-Cl-C6H4CH2NH2
4-F-C6H4CH2NH2
4-F-C6H4CH2NH2
4-F-C6H4CH2NH2
4-MeO-C6H4CH2NH2
4-MeO-C6H4CH2NH2
4-CF3-C6H4CH2NH2
4-CF3-C6H4CH2NH2
4-CF3-C6H4CH2NH2
3-CF3-C6H4CH2NH2
3-CF3-C6H4CH2NH2
3-CF3-C6H4CH2NH2
3-F-C6H4CH2NH2
3-F-C6H4CH2NH2
3-F-C6H4CH2NH2
3-Me-C6H4NH2
F
Cl
2f
1g
2g
3g
1h
2h
3h
1i
F
Me
Cl
F
Me
Cl
F
2i
Me
F
3i
1j
Me
Cl
2j
1k
2k
3k
1l
F
Me
Cl
F
2l
Me
Cl
3l
1m
2m
3m
1n
2n
3n
F
Me
Cl
F
Me
3-Me-C6H4NH2
3-Me-C6H4NH2
aYields determined by GC.
bDetermined by 1HNMR and NOESY.

´
´
M. AMEZQUITA-VALENCIA, G. A. SUAREZ-ORTIZ, AND A. CABRERA
1952
Figure 1. X-ray structures of 2c, 4c, 4d, 1k, and 2n compounds, with thermal ellipsoids drawn at 40%.
Table 4. Synthesis of various imines catalyzed by Mg(ClO4)2
Entrya,b
Ketone
Amine
Product
Yieldc (%)
89
1
C6H5CH2NH2
1o[28]
2
3
p-CH3O-C6H4NH2
m-Cl-C6H4NH2
2o[29]
90
86
3o
4
5
6
7
C6H5CH2NH2
p-ClC6H4CH2NH2
C6H5CH2NH2
C6H5CH2NH2
1p
2p
89
87
82
81
1q
1r[30]
8
C6H5CH2NH2
1s[31]
60
aReaction with Na2SO4.
b5 mL of dry DCE.
cYields determined by GC.

SYNTHESIS OF PROCHIRAL IMINES
1953
enhanced conversion rate compared to aniline precursors because of the different
basic nature of the nitrogen atom present in their respective functional groups.
The high functional group tolerance of the catalytic system demonstrated by the suc-
cessful use of aryl, alkyl, cyclo, heterocyclic, and ferrocenyl ketones in the synthesis
of prochiral imines is shown in Table 4. By this general reaction, we developed an
efficient methodology for the preparation of ketoimines in good yields, which gives
a good account of the scope of the process. Finally, the synthesized compounds are
attractive for the synthesis of chiral secondary amines.
EXPERIMENTAL
Melting points were determined in a Fisher Scientific electrochemical Mel-
Temp manual melting-point apparatus (model 1001D) equipped with a 300 ꢀC
thermometer. Fourier transform–infrared (FT-IR) spectra were registered on an
IR spectra recorded on a Bruker-Alpha ATR apparatus. All NMR spectra were
recorded on a Jeol GX300 (1H at 300.53 MHz) spectrometer in CDCl3. Suitable
crystals were grown from hexane, and in all cases, the x-ray intensity data were mea-
sured at 298 K on a Bruker Smart Apex CCD-based x-ray diffractometer system
˚
equipped with a Mo-target x-ray tube (0.71073 A). Mass spectra were obtained using
a Jeol JMSAX505HA spectrometer. All reactions were monitored on a Hewlett
Packard 5890 series gas chromatograph equipped with a flame ionization detector
using a HP-ultra 2 column 25 m long.
Typical Procedure for Synthesis of Imines
A mixture of 1.0 mmol of ketone and 1.1 mmol of amine in 5 ml of dried DCE
was stirred and refluxed for 12 h in the presence of 3% mol of Mg(ClO4)2.[27] At the
end of reaction time, the mixture was diluted with 5 mL of DCE to facilitate the
workup and filtered to remove the precipitated Mg(ClO4)2in the presence of
Na2SO4as drying agent The solvent was evaporated, and the product was purified
by column chromatography over neutral alumina with hexane=dichloromethane as
eluent.
Complete experimental and spectral details are available online in the
Supplemental Material.
ACKNOWLEDGMENTS
We thank DGAPA-UNAM (PAPIIT IN203209) and CONACyT (Fellowship
229448) for financial support. Also, we gratefully acknowledge A. Toscano, S.
´
Hernandez-Ortega, J. Perez, and L. Velasco for technical support.
´
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