Iron-catalyzed direct synthesis of imines from amines or alcohols and amines via aerobic oxidative reactions under air

Article abstract of DOI:10.1021/ol4010118

Abundant and cheap iron readily catalyzed the aerobic oxidative reactions of primary amines, secondary amines, benzylamines with anilines, and alcohols with amines by directly using air as the economic and safe oxidant, providing several direct, practical, and greener approaches for the preparation of useful imines.

Full text of DOI:10.1021/ol4010118

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iron-Catalyzed Direct Synthesis of Imimes
from Amines or Alcohols and Amines via
Aerobic Oxidative Reactions under Air
Erlei Zhang, Haiwen Tian, Sendong Xu, Xiaochun Yu, and Qing Xu*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang 325035, China
qing-xu@wzu.edu.cn
Received April 11, 2013
ABSTRACT
Abundant and cheap iron readily catalyzed the aerobic oxidative reactions of primary amines, secondary amines, benzylamines with anilines, and
alcohols with amines by directly using air as the economic and safe oxidant, providing several direct, practical, and greener approaches for the
preparation of useful imines.
Since they bear the reactive CdN bond and are capable
of undergoing various types of transformations, imines are
versatile nitrogen sources and reactive intermediates in the
synthesis of a wide range of biologically and pharmaceuti-
cally active compounds, heterocycles, and natural products.1
Since the traditional condensation method2 suffers from the
drawbacks of using the odorous and unstable aldehydes
that also require in situ purification prior to use, developing
efficient and greener methods is still an important task in
current imine chemistry.3À11 Although the methods for
imine preparation have now been greatly improved,3À11
especially by employing the one-pot tandem reactions of
amines with the greener, cheaper, and more available
alcohols4,6,8,10 and direct oxidation of the amines,5,7,9,11
drawbacks still remain and many issues have yet to be
satisfactorily addressed. For example, early methods re-
quire large excess amounts of oxidants, which will also
produce large amounts of undesired waste.4,5 The dehy-
drogenation methods are highly atom economic, but they
suffer from the use of active, sensitive, expensive, and
capricious ligands; not easily accessed noble metal com-
plexes; and harsh reaction conditions such as high reaction
temperatures and inert atmosphere protection.6,7 In con-
trast, the aerobic oxidative reactions are comparatively
greener, more preferable, and more practical methods
because of the use of pure oxygen or air as the pollution-
free oxidant, much more easily disposable catalysts, and
milder reaction conditions, along with generating water as
the byproduct.8À11 However, withonly a few exceptions,8,9
most reactions still require high reaction temperatures,
expensive and rare noble metal catalysts, special conditions,
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r
10.1021/ol4010118
XXXX American Chemical Society

or dangerous pure oxygen as the oxidant.10,11 To our
knowledge, the cheaper, more available, and nontoxic
metals such as iron have not been successfully used in the
methods yet.12 Herein we report that a general Fe(NO3)3/
TEMPO system can readily catalyze the aerobic oxidative
reactions of 1° and 2° amines, different amines, and alcohols
with amines by using air as the oxidant, providing several
greener and more practical approaches for the preparation
of useful imines.
In previous stuides on aerobic oxidative reactions of
alcohols with amides and amines,8,9d,10c,13 we noticed that
the versatile metal Fe14 is also a good catalyst for the aerobic
oxidation of alcohols.15 Since an Fe-catalyzed method was
not known yet, we envisoned that, if Fe is also a good
catalyst for imine synthesis through aerobic oxidative
reactions of alcohols and amines or directly the amines, it
may become a potentially more advantageous and more
practical catalyst than other metals due to its abundance in
the Earth’s crust, high availability, low price, and also
possibly its nontoxic and biofriendly properties.
Thus, the Fe-catalyzed oxidation of primary amine 1a
was first investigated under air (Table 1). Preliminary
screening on Fe catalysts and reaction temperatures
showed that various Fe catalysts [FeCl3, FeBr3, Fe2O3,
Fe2(SO4)3, Fe(NO3)3] (5 mol %) could catalyze the reac-
tion alone without any ligands, bases, or additives.16 Fe-
(NO3)3 was in comparison the best catalyst and 80 °C an
appropriate temperature for the reaction, giving an acce-
patble yield of target imine 2a (run 1).17 Additives were
then employed to improve the reaction efficiency.16 We
were pleased to find that the addition of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxyl, 3 mol %) could greatly en-
hance the product yield to 85% (run 2) as in other catalytic
systems.8À11 In contrast, the reaction with 3 mol % of
TEMPO alone was rather ineffective under the same condi-
tions (run 3), indicating the key role of Fe in catalyzing the
reaction.17 Further condition screening by investigating the
effects of catalyst loadings, Fe catalyst and TEMPO combi-
nations, solvents, and temperatures16 revealed that xylene and
dioxane are also suitable solvents, and using both 5 mol % of
Fe(NO3)3 and TEMPO in toluene at 80 °C was optimal for
the reaction, giving almost full conversion of 1a and a good
isolated yield of 2a (run 4).
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Yu, X.; Xu, Q. Tetrahedron Lett. 2013, 54, 2861.
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Park, J. J. Org. Chem. 2009, 74, 2877. (b) Sun, H.; Su, F.-Z.; Ni, J.; Cao,
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Table 1. Condition Optimization for Fe-Catalyzed Aerobic
Oxidation of Benzylamine to Imine under Aira,16
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run
[Fe] (mol %)b
additive (mol %)
2a %c
1
2
3
4
Fe(NO3)3 (5)
Fe(NO3)3 (5)
À
À
66
TEMPO (3)
TEMPO (3)
TEMPO (5)
85
8
Fe(NO3)3 (5)
97 (82)
a The mixture of 1a (2 mmol), Fe catalyst, and additives in toluene
(0.5 mL) was heated under air in a 100 mL tube at 80 °C for 24 h and then
ꢀ
Sato, H.; Nakae, T.; Komiya, N. Synlett 2007, 1675. (k) Samec, J. S.; Ell,
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A. H.; Backvall, J.-E. Chem.;Eur. J. 2005, 11, 2327.
monitored by TLC and/or GC-MS. b Fe(NO3)3 9H2O was used and
(12) Recently Zhang and Hanson reported a cobalt-complex-catalyzed
anaerobic alcohol dehydrogenation method and applied it in the synthesis of
imines (ref 6e), which may still suffer from cobalt’s toxicity and the catalyst’s
sensitivity, availability, and price.
3
abbreviated. c GC yields (isolated yields in parentheses) based on 1a.
(13) (a) Liu, C.; Liao, S.; Li, Q.; Feng, S.; Sun, Q.; Yu, X.; Xu, Q.
J. Org. Chem. 2011, 76, 5759. (b) Yu, X.; Liu, C.; Jiang, L.; Xu, Q. Org.
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Org. Biomol. Chem. 2012, 10, 2966.
The optimized conditions (Table 1, run 4) were then
applied to various primary and secondary amines by using
the Fe(NO3)3/TEMPO catalyst system (Table 2). The
results showed that the method tolerates various func-
tional groups. It should be mentioned that nitriles and
amides, which might be generated as the byproducts in
other catalytic systems,5,7,9,11 were not detected at all in
the present reactions, revealing the high imine selectivity
and another advantage of using Fe(NO3)3/TEMPO as the
catalyst. Thus, both electron-rich (runs 1À6) and -deficient
(runs 7À13) benzylamines, including the sterically more
(14) (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. Rev. 2004,
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Rev. 2011, 111, 1293.
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Wan, B.; Wang, Y.; Ye, J.; Yu, Q.; Yuan, W.; Yu, S. Adv. Synth. Catal.
2011, 353, 1005. (b) Xue, G.; Pokutsa, A.; Que, L., Jr. J. Am. Chem. Soc.
2011, 133, 16657. (c) Miao, C.-X.; Wang, J.-Q.; Yu, B.; Cheng, W.-G.;
Sun, J.; Chanfreau, S.; He, L.-N.; Zhang, S.-J. Chem. Commun. 2011, 47,
€
2697. (d) Al-Hunaiti, A.; Niemi, T.; Sibaouih, A.; Pihko, P.; Leskela, M.;
(16) See Supporting Information for details.
(17) Fe(NO3)3 alone could give >99% GC yield of 2a under O2.
Repo, T. Chem. Commun. 2010, 46, 9250. (e) Yin, W.; Chu, C.; Lu, Q.;
Tao, J.; Liang, X.; Liu, R. Adv. Synth. Catal. 2010, 352, 113.
B
Org. Lett., Vol. XX, No. XX, XXXX

hindered ortho-substituted ones (runs 3, 6, 9, 11, 13),
reacted efficiently to give the target imines in good yields.
The halo-substituted imines 2hÀn are potentially useful in
thesynthesis, astheybearfluoroand chlorogroups andthe
reactive CdN bond. In contrast to benzylamines, the reac-
tion of a heterobenzylamine 1o was not efficient (run 14),
and the product could not be isolated in pure form due to
easy hydrolysis during purification, even with the use
preneutralized silica gel.18 Similarly, aliphatic amines are
also not suitable substrates, and only trace products were
detected (runs 15À16).18
and 1,2,3,4-tetrahydroisoquinoline (1r) could be readily
oxidized to indole (2q) and 3,4-dihydroisoquinoline (2r) in
moderate yields, respectively (runs 18, 19). In contrast, the
oxidation of 1,2,3,4-tetrahydroquinoline (1s) was more
difficult, giving aromatized quinoline (2s) in only a low
yield (run 20).
The similar method could also be applied to the reac-
tions of benzylamines and anilines to synthesize the cross
imines. Condition screening showed that 5 mol % of either
Fe or TEMPO, or both 5 mol % of Fe and TEMPO, and a
1/1 molar ratio of 1a and aniline only resulted in incom-
plete conversion of the substrates and formation of the
undesired byproduct 2a in large amounts.16 Then, by using
both 10 mol % of Fe and TEMPO and slight excess amounts
of aniline (1.2 equiv), the full conversion of 1a, with high
selectivity (95%) and a good isolated yield (71%), to the
target imine 3a was achieved (Scheme 1). This method can be
extended to different benzylamines and anilines. Thus, under
the same conditions, cross imines 3bÀc were also obtained in
high selectivities and good yields from the reactions of
corresponding benzylamines and anilines (Scheme 1).
Table 2. Fe-Catalyzed Aerobic Oxidation of Primary and
Secondary Amines to Imines under Aira
Scheme 1. Fe-Catalyzed Aerobic Oxidation of Benzylamines
and Anilines to Cross Imines under Air16
Since alcohols are generally known as much greener
chemicals due to their wide scope, high availability, low
price, and low toxicity,19 we then turned to investigate the
Fe-catalyzed aerobic reactions of alcohols and amines
under air, which, if achieved, should be a comparatively
more advantageous method than the above cross reactions
of different amines. Therefore, the same catalyst was first
applied to the reaction of 1a and benzyl alcohol (4a) to
optimize the condition (Table 3). However, only a low
yield of the target imines 2a was detected along with large
amounts of unreacted 4a and the formation of benzalde-
hyde as the byproduct (run 1). Like most of the known
imination reactions of alcohols and amines,6,10 it was then
found that the base played a crucial role in the reaction. As
shown in Table 3, the reaction was initially tested at room
temperature with a catalytic amount of KOH added, but
only a low yield of 2a was detected (run 2). This result was
then gradually improved by heating the reaction at higher
temperatures or adding more KOH (runs 3À5). Thus,
nearly full conversion of 1a (97%) and a good isolated
a The mixture of 1 (2 mmol), Fe(NO3)3 9H2O (5 mol %), TEMPO
(5 mol %) in toluene (0.5 mL) was heated under air in a 100 mL tube at
3
80 °C for 24 h and then monitored by TLC and/or GC-MS. b GC yields
(isolated yields in parentheses) based on 1. c Fe(NO3)3 9H2O (10 mol %),
3
TEMPO (10 mol %), 120 °C, 24 h.
The Fe-catalyzed aerobic oxidation method was then
applied to secondary amines. It seemed the present method
was not suitable for simple secondary amines such as
dibenzyl amine (1p), for only a low yield of the product
was obtained under harsher reaction conditions (run 17).
Contrarily, cyclic secondary amines such as indoline (1q)
(18) Despite that we tried many attempts, these imines could not be
isolated in pure form due to easy hydrolysis during purification. See: (a)
Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem.
Commun. 2003, 2462. (b) Lee, A. V.; Schafer, L. L. Organometallics 2006,
25, 5249. (c) Burland, P. A.; Coisson, D.; Osborn, H. M. I. J. Org. Chem.
(19) (a) Watson, A. J. A.; Williams, J. M. J. Science 2010, 329, 635. (b)
Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681. (c)
Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611. (d)
Emer, E.; Sinisi, R.; Capdevila, M. G.; Petruzziello, D.; De Vincentiis,
F.; Cozzi, P. G. Eur. J. Org. Chem. 2011, 647. (e) Zhang, S.-Y.; Zhang,
F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40, 1937. (f) Xu, Q.; Li, Q. Chin.
J. Org. Chem. 2013, 33, 18.
ꢀ
ꢀ
2010, 75, 7210. (d) Monnereau, L.; Semeril, D.; Matt, D. Green Chem.
2010, 12, 1670. (e) References 9 and 11.
Org. Lett., Vol. XX, No. XX, XXXX
C

yield of 2a (78%) could be achieved at 80 °C by using
20 mol % of KOH as the base (run 5).
Table 3. Condition Optimization for Fe-Catalyzed Aerobic
Oxidation of Benzyl Alcohol and Benzylamine under Aira
The optimized conditions were then applied to various
alcohols and amines to extend the scope of the method
(Table 4). Similarto1a, the reaction of2-phenylethylamine
(5a) was also efficient under the same conditions and gave
a moderate yield of the target imine 6aa (run 1). In contrast,
the reactions of aliphatic amines were not efficient, affording
only low yields of the products under similar conditions
(runs 2À4). We then focused on the reactions of anilines to
synthesize useful aromatic imines. However, possibly be-
cause the anilines are less basic and less nucleopilic, only a
36% yield of 3a was detected under the conditions for benzyl-
amine.16 Further condition screening showed that 30À
50 mol % of KOH, CsOH, and t-BuOK were the most
effective for the reaction (e.g., 91À96% GC yields of 3a),16
and a good isolated yield of 3a could be obtained (run 5).
Similarly, both electron-rich and -deficient benzylic alcohols,
including a sterically more bulky ortho-substituted 4g (run 11)
and a heterobenzylic alcohol 4j (run 14), reacted efficiently
with 5e to afford the target imines in moderate to good yields
(runs 6À14). The reactions of an aliphatic alcohol and a
secondary benzilic alcohol were also tested under the same
condtions, but they were not successful (runs 15, 16).
Besides, this method is applicable to various electron-rich
and -deficient anilines, including sterically more bulky
ortho-subsituted 5h (run 19) and 1-naphthylamine 5k
(run 27), giving moderate to good yields of the products
(runs 17À27). It seemed the electron-rich anilines were
better substrates, for they generally gave higher yields of
the products (runs 17À25) than the electron-deficient one
(run 26). The reaction of 1-naphthylamine 5k was less
efficient than the anilines under the same conditions, and
CsOH had to be used as the base instead of KOH (run 27).
In summary, by using the general Fe(NO3)3/TEMPO
catalyst system, we developed several Fe-catalyzed methods
for the preparation of useful imines by aerobic oxidation
reactions of primary amines, secondary amines, benzylamines
with anilines, and alcohols with amines. Since abundant,
cheap, and relatively more biofriendly iron can be readily
used as the catalyst and air as the economic and safe
oxidant, these aerobic methods may become green and
practical alternatives for the direct synthesis of imines from
amines and alcohols. Further extension of the Fe-catalyzed
aerobic oxidative method and mechanistic studies of the
reactions are underway.
run
base (mol %)
temp
2a %b
1c
2
À
80 °C
rtd
45
KOH (10)
KOH (10)
KOH (10)
KOH (20)
29
3
50 °C
80 °C
80 °C
53
4
70
5
97 (78)
a The mixture of 1a (1 mmol), 4a (1.2 mmol), Fe(NO3)3 9H2O
3
(10 mol %), TEMPO (10 mol %), and the base in toluene (0.5 mL)
was heated under air in a 100 mL tube for 24 h and then monitored by
TLC and/or GC-MS. b GC yields (isolated yields in parentheses) based
on 1a. c ∼10% PhCHO (based on 4a) was detected as the byproduct. A
large amount of 4a remained unreacted. d Ca. ∼30 °C.
Table 4. Fe-Catalyzed Aerobic Oxidative Reactions of Alcohols
and Amines to Imines under Aira
run
4, 5
3 or 6: yield %b
1c
4a, PhCH2CH2NH2 (5a)
4a, n-C4H9NH2 (5b)
4a, c-C6H12NH2 (5c)
4a, t-C4H9NH2 (5d)
4a, PhNH2 (5e)
6aa: 84 (61)
6ab: (32)
2c,d
3c,d
4c,d
5e
6ac: (41)
6ad: 19
3a: 96 (75)
6be: 91 (77)
3c: 94 (83)
6de: 83 (67)
6ee: 89 (70)
6fe: 92 (76)
6ge: 98 (81)
6he: 96 (82)
6ie: 80 (62)
6je: 90 (78)
À
6e
p-MeC6H4CH2OH (4b), 5e
m-MeOC6H4CH2OH (4c), 5e
p-FC6H4CH2OH (4d), 5e
p-ClC6H4CH2OH (4e), 5e
m-ClC6H4CH2OH (4f), 5e
o-ClC6H4CH2OH (4g), 5e
p-BrC6H4CH2OH (4h), 5e
p-NO2C6H4CH2OH (4i), 5e
2-thiophenemethanol (4j), 5e
n-C6H13OH (4k), 5e
PhCH(CH3)OH (4l), 5e
4a, p-MeC6H4NH2 (5f)
4a, m-MeC6H4NH2 (5g)
4a, o-MeC6H4NH2 (5h)
4a, p-EtOC6H4NH2 (5i)
4b, 5i
7e
8e
9e
10e
11e
12e
13e
14e
15e
16e
17e
18e
19e
20e
21e
22e
23e
24e
25e
26e
27e,f
À
6af: 75 (58)
6ag: 76 (61)
6ah: 70 (63)
3b: 95 (82)
6bi: 99 (75)
6ei: 91(78)
6gi: 95 (85)
6hi: 81 (64)
6ji: 71 (57)
6aj: 70 (56)
6ak: 59 (43)
4e, 5i
Acknowledgment. We thank ZJNSF (LY13B020006,
Y4100579), SRF for ROCS of SEM, ZJQJTP (QJD0902004),
and Postgraduate Innovation Foundation of Wenzhou Univer-
sity (31606036010193) for financial support.
4g, 5i
4h, 5i
4j, 5i
4a, p-ClC6H4NH2 (5j)
4a, 1-naphthylamine (5k)
Supporting Information Available. Experimental pro-
cedures, detailed condition screening tables, product
a Unless otherwise noted, the mixture of 4 (1.2 mmol), 5 (1 mmol),
Fe(NO3)3 9H2O (10 mol %), TEMPO (10 mol %), and KOH in toluene
(0.5 mL) was heated under air in a 100 mL tube at 80 °C and then
monitored by TLC and/or GC-MS. b GC yields (isolated yields in
parentheses) based on 5. c 20 mol % KOH, 24 h. d 1 mmol 4 and 2 mmol
5 were used; yields were based on 4. e 50 mol % KOH, 36 h. f CsOH
(50 mol %) used instead of KOH.
3
1
characterization, and H and 13C NMR spectra of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX