NaOH-catalyzed imine synthesis: Aerobic oxidative coupling of alcohols and amines

Article abstract of DOI:10.1002/ejoc.201200716

The convenient transition-metal-free synthesis of imines through oxidative coupling of alcohols and amines is reported. The reaction is catalyzed by NaOH (10 mol-%) and is performed with air as an oxidant in the absence of any co-solvent. The convenient transition-metal-free synthesis of imines through oxidative coupling of alcohols and amines is reported. The reaction is catalyzed by NaOH (10 mol-%) and is performed with air as an oxidant in the absence of any co-solvent. Copyright

Full text of DOI:10.1002/ejoc.201200716

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200716
NaOH-Catalyzed Imine Synthesis: Aerobic Oxidative Coupling of Alcohols
and Amines
Ramachandra Reddy Donthiri,[a] Rajendra D. Patil,[a] and Subbarayappa Adimurthy*[a]
Keywords: Imines / Oxidative coupling / Heterogeneous catalysis / Amines / Alcohols
The convenient transition-metal-free synthesis of imines
through oxidative coupling of alcohols and amines is re-
ported. The reaction is catalyzed by NaOH (10 mol-%) and
is performed with air as an oxidant in the absence of any co-
solvent.
of prime interest in our laboratory.[4] Herein, we demon-
strate that it is possible to realize the direct synthesis of
imines from primary alcohols and amines [Equation (1)] in
the presence of sodium hydroxide as a heterogeneous cata-
lyst (10 mol-%).
Introduction
Imines are a very important class of compounds in chem-
istry as well as biology that have widely been utilized as
intermediates in the synthesis of nitrogen heterocycles, fine
chemicals, and pharmaceuticals.[1] Significant progress has
been made in recent years, including the direct synthesis of
imines through oxidative self-condensation of primary and
secondary amines.[2] The coupling of alcohols and amines
in the presence of oxidants is also a commonly utilized pro-
cedure.[3] The synthesis of imines starting from alcohols and
amines has major advantages, because of their potential ap-
plications and wide substrate scope. Alcohols are desirable
starting materials because they are readily available, inex-
pensive, and theoretically produce only hydrogen or water
as a byproduct.
Many research groups have reported the direct synthesis
of imines through the coupling of alcohols and amines. In
2010, Milstein and co-workers reported the direct synthesis
of imines from primary alcohols and amines using a PNN
pincer-type ruthenium complex.[3e] Although, these meth-
ods are highly efficient,[3] the procedure is disadvantageous
because access to such precious and heavy metals is limited
by the availability of the natural resources. Therefore, the
development of new environmentally friendly procedures
for the synthesis of imines is a very important subject in
modern organic synthesis.
Initially, benzyl alcohol (1a) and aniline (2a) were sub-
jected to oxidative imination by using sodium hydroxide
(100 mol-%) as a catalyst at 100 °C in an open atmosphere;
52% conversion of aniline to imine 3a with 88% selectivity
was observed after 20 h (Table 1, entry 1). Surprisingly,
when the transformation was carried out using 10 mol-% of
sodium hydroxide, 97% conversion of aniline was observed
with 94% yield of imine 3a (Table 1, entry 2). To optimize
the reaction conditions, we screened different catalysts, tem-
perature, and solvents. After extensive screening of various
catalysts (Table 1), 10 mol-% NaOH at 100 °C in air were
set as the optimized reaction conditions for the present in-
vestigation for the synthesis of other imines. To the best of
our knowledge, this is the first convenient transition-metal-
free process reported for the efficient oxidative synthesis of
imines from alcohols and amines using air as the oxidant
without any co-solvent. Under the optimized conditions
(Table 1, entry 2) a range of structurally diverse primary
benzylic alcohols were examined. NaOH showed high cata-
lytic activity for the transformation of benzylic and hetero-
atom-containing alcohols (Table 2).
The reaction of 1a with aromatic amines 2a–e containing
electron-donating as well as electron-withdrawing substitu-
ents in the para position efficiently proceeded to afford the
corresponding substituted imine derivatives in excellent
yields (86–99%). ortho-Substituted anilines 2f and 2g gave
moderate to good yields of the corresponding imines. This
may be due to the steric hindrance of the ortho-substituent
groups. However, amines such as 1-naphthyl 2h, benzyl 2i,
aryl aliphatic 2j, and aliphatic n-heptyl 2k and n-decyl 2l
afforded the corresponding imines in excellent yields.
Results and Discussion
The activation of alcohols and/or amines to their corre-
sponding oxidized products under sustainable conditions is
[a] Analytical Science Division,
Central Salt & Marine Chemicals Research Institute, (CSIR),
G.B. Marg, Bhavnagar-364021 India
Fax: +91-278-2567562
E-mail: adimurthy@csmcri.org
Homepage: http://www.csmcri.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200716.
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R. R. Donthiri, R. D. Patil, S. Adimurthy
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions for imine synthesis.[a]
Table 2. Scope of the reaction for the synthesis of imines from
alcohols and amines.[a]
[a] Reaction conditions: 1 (6 mmol), 2 (2 mmol), 100 °C, open at-
mosphere. [b] Isolated yield; numbers in parentheses refer to yield
based on GC area %. [c] See ref.[5] [d] 80% benzophenone was
isolated.
shown). Finally, the oxidative condensation of a secondary
alcohol such as diphenylmethanol (1h) with aniline (2a) was
attempted, but the reaction did not proceed. Instead of the
desired ketimine, 80% of benzophenone was isolated
(Table 2, entry 21).
Based on experimental observations and literature re-
ports, we propose a probable mechanism for the present
transformation (Scheme 1).[3,6,7] The transition-metal-cata-
lyzed oxidative coupling of alcohols and amines leading to
imines is well studied. In such transformations, a likely
mechanism is β-hydride elimination from the alcohol by the
transition metal catalyst to generate a metal hydride inter-
mediate, which subsequently provides the aldehyde.[3] The
[a] Reaction conditions unless otherwise stated: 1a (6 mmol), 2a
(2 mmol), 100 °C, 20 h, open atmosphere. [b] Conversion with re-
spect to amine. [c] Based on GC area %. [d] 100 mol-% catalyst
used. [e] In entries 3, 8–13, 1a/2a = 1:1, whereas in entry 4, 1a/2a
= 2:1. [f] Reaction carried out for 24 h. [g] Reaction carried out at
r.t. (entry 6) and at 65, 90, and 70°C in entries 7, 8, and 13, respec-
tively. [h] Reaction carried out under O2 atmosphere (entry 14) and
N2 atmosphere (entry 15). NHS = N-Hydroxysuccinimide.
Next, the scope of the present transformation was ex- aerobic base-catalyzed transition-metal-free oxidation of
tended to substituted benzylic alcohols 1b–f. The reaction alcohols has been reported.[7] The generation of metal hy-
of benzylic alcohols 1b–f containing electron-donating as drides using alkali ions was seldom observed under our
well as electron-withdrawing substituents at different posi- conditions. Moreover, the reaction of benzyl alcohol in the
tions reacted smoothly with different amines and afforded absence of an amine does not lead to the aldehyde [Equa-
the corresponding substituted imine derivatives 3m–s in tion (2)]. Therefore, we propose that activation of the
good to excellent yields (78–87%). Heteroatom-containing alcohol by NaOH in the presence of an amine and oxygen
alcohol such as pyridine 1g afforded the corresponding het- likely results in the generation of an aldehyde intermediate
eroaromatic imine 3t in a moderate yield of 43%. The reac- (Scheme 1). The aldehyde reacts with the amine to yield the
tion of aliphatic (n-butanol) and allylic alcohol with aniline imine with simultaneous regeneration of NaOH through
(2a) failed to afford the corresponding imines (data not NaOOH/H2O.[8] The conversion of diphenylmethanol (1h)
2
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NaOH-Catalyzed Imine Syntheses
(0.19 g, 2 mmol) at room temperature. The resulting reaction mix-
ture was heated at 100 °C for 20 h in an open atmosphere. The
progress of the reaction was monitored by TLC. After completion
of reaction, the reaction mixture was filtered through Whatman
filter paper, and the residue was washed with diethyl ether (3ϫ
5 mL). The filtrates were collected and dried with anhydrous so-
dium sulfate. [The sample taken from the filtrate was analyzed by
GC–MS analysis, which showed 94% yield of imine 3a]. The filtrate
was concentrated in vacuo, and the residue left out was subjected to
column chromatography on neutral alumina (ethyl acetate/hexane).
into benzophenone (3u) under the present optimized condi-
tions also supports the generation of an aldehyde (Table 2,
entry 21). To check further, we performed a standard reac-
tion of benzophenone and aniline under similar experimen-
tal conditions, but only a trace amount of the imine was
observed. It may possible that the presence of trace
amounts of transition metals in commercial available
NaOH may be responsible for the catalytic activity. To
check the hypothesis, related catalytic such as pure Na
metal and NaH (Supporting Information, Table S1, en- Pure imine product 3a (0.25 g; 1.4 mmol) was obtained in 70%
yield. All reactions were carried out in air without any special pre-
cautions.
tries 6 & 7) were also examined. These species provided
yields and selectivities for the imines that were similar to
those obtained with NaOH. Finally, to confirm, we per-
formed the reaction with the preformed sodium alkoxide
N-(4-Chlorobenzylidene)-4-ethylaniline: Table 2, entry 19. 1H NMR
(500 MHz, CDCl3): δ = 1.23 (t, J = 8 Hz, 3 H), 2.62 (q, J = 8 Hz,
of benzyl alcohol, which also showed excellent yield and 2 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 7.40 (d,
J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 8.40 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 17, 29.8, 122.3, 130, 130.4, 131.2,
selectivity (Supporting Information, Table S1, entry 8).
These facts show that a sodium alkoxide may form as an
intermediate species. They also support the catalytic activity
of NaOH and the probability that trace amounts of metal
catalysts play a role is low.
136.2, 138.5, 143.9, 156.6, 159.4 ppm. IR (Neat): ν = 3062, 2967,
˜
2927, 2872, 2360, 1911, 1623, 1588, 1494, 1459, 1405, 1359, 1167,
1086, 1010, 971, 837, 678, 563, 535, 507 cm–1. C15H14ClN (243.74):
calcd. C 73.92, H 5.79, N 5.75; found C 73.27, H 5.71, N 5.30.
GC–MS: m/z (%) = 243 (65) [M]+, 228 (100), 165 (7), 103 (7), 89
(20), 77 (20), 63 (7), 51 (11), 39 (7).
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR, 13C NMR, and GC–MS spectra.
Acknowledgments
We thank Mr. Hitesh/Dr. A. V. Boricha & Ms. Jigna, Analytical
Division of this institute for supporting NMR and GC–MS analy-
ses, respectively. D. R. R. and R. D. P. are thankful to the Univer-
sity Grants Commission (UGC) and the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for their JRF and
SRF award, respectively. S. A. thanks the CSIR/CSMCRI for in-
ternal grants.
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Conclusions
In conclusion, we have developed a green and efficient
protocol for the synthesis of imines through the oxidative
coupling of alcohols and amines. The reactions proceed
without any transition metal, ligand, or co-solvent under
aerobic conditions. The present protocol is applicable to a
variety of alcohols and amines and offers an environmen-
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The method has versatile scope for various benzyl alcohols
and amines with, however, some limitations for aliphatic
alcohols.
Experimental Section
Typical Procedure for the Synthesis of N-Benzylideneaniline 3a: So-
dium hydroxide (8.0 mg, 0.2 mmol) was added to a two-necked
round-bottomed flask containing 1a (0.65 g, 6 mmol) and 2a
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SHORT COMMUNICATION
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azobenzene (Supporting Information, Table S1, entry 4). The
related catalytic species NaH and Na metal (Supporting Infor-
mation, Table S1, entries 6 & 7) were also examined; however,
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[8] Generation of NaOOH in related reactions has been reported
(see ref.[7b]).
Received: May 29, 2012
Published Online: ᭿
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NaOH-Catalyzed Imine Syntheses
Imine Synthesis
The convenient transition-metal-free syn-
thesis of imines through oxidative coupling
of alcohols and amines is reported. The re-
action is catalyzed by NaOH (10 mol-%)
and is performed with air as an oxidant in
the absence of any co-solvent.
R. R. Donthiri, R. D. Patil,
S. Adimurthy* ................................... 1–5
NaOH-Catalyzed Imine Synthesis: Aerobic
Oxidative Coupling of Alcohols and
Amines
Keywords: Imines / Oxidative coupling /
Heterogeneous catalysis / Amines / Al-
cohols
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