Transition Metal-Free Oxidative Coupling of Primary Amines in Polyethylene Glycol at Room Temperature: Synthesis of Imines, Azobenzenes, Benzothiazoles, and Disulfides

Article abstract of DOI:10.1002/ejoc.201801610

A transition metal-free protocol has been developed for the oxidative coupling of primary amines to imines and azobenzenes, thiols to disulfides, and 2-aminothiophenols to benzothiazoles, offering excellent yields. The advantageous features of the present environmentally benign methodology include the usage of biocompatible and green reaction conditions such as, solvent, room temperature reactions and transition metal-free approach. Moreover, it offers a broader substrate scope.

Full text of DOI:10.1002/ejoc.201801610

A Journal of
Accepted Article
Title: Transition Metal-Free Oxidative Coupling of Primary Amines in
Polyethylene Glycol at Room Temperature: Synthesis of Imines,
Azobenzenes, Benzothiazoles and Disulfides
Authors: Abhinandan D Hudwekar, Praveen Kumar Verma, Jaspreet
Kour, Shilpi Balgotra, and Sanghapal D. Sawant
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801610
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801610
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10.1002/ejoc.201801610
European Journal of Organic Chemistry
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Transition Metal-Free Oxidative Coupling of Primary Amines in
Polyethylene Glycol at Room Temperature: Synthesis of Imines,
Azobenzenes, Benzothiazoles and Disulfides
Abhinandan D. Hudwekar,[a,b] Praveen K. Verma,[a] Jaspreet Kour,[a,b] Shilpi Balgotra,[a,b] and
Sanghapal D. Sawant*[a,b]
Abstract: A transition metal-free protocol has been developed for
synthesis of azobenzenes from amines including stoichiometric
the oxidative coupling of primary amines to imines and azobenzenes, amount of reagents with toxic transition metals, or through
thiols to disulfides and 2-aminothiophenols to benzothiazoles
offering excellent yields. The advantageous features of the present
environmentally benign methodology includes the usage of
biocompatible and green reaction conditions like solvent, room
temperature reactions, transition metal-free approach and moreover,
it offers broader substrate scope.
diazonium coupling using stoichiometric amounts of nitrite salts.
Numerous metal promoted methodologies have also been
developed for the synthesis of azo compounds (Scheme 1).[8] It
has been observed that sometime the redox pathway of nitro
and amino compounds proceed via azo compounds as one of
the intermediates, hence, it is a challenging task to control the
selectivity for azo intermediates.[8f]
Herein, we have developed a new transition metal-free
approach for the oxidative coupling of alkyl amines to imines and
Introduction
aryl amines to azobenzenes in
a green solvent system,
polyethylene glycol (PEG 200) at room temperature. In recent
years, PEG has attracted special interest as a biodegradable,
Imines[1] and azobenzenes[2] are very important functional
moieties having diverse applications in the fields of
thermally
stable,
non-volatile,
environment
friendly,
biocompatible, green, inexpensive reaction medium.[9] The
remarkable finding of the present protocol is the synthesis of
symmetrical as well as unsymmetrical imines and azobenzenes.
In extension to this, the oxidative coupling of benzylamines with
ortho-thio substituted anilines leads to the formation of
corresponding benzothiazoles and oxidative self coupling of
thiols afforded disulfides under same reaction conditions. Thus,
present methodology extends broader scope and applications in
the area of organic synthesis.
pharmaceuticals,
biologicals,
agrochemicals,
dyes,
polymerization, and as electrophiles for various transformations.
These are also perceived as imperative intermediates during
some chemical conversions and as synthones for the
preparation of complex molecules.[3] Recent applications[3] of azo
compounds included as radical initiator in photodynamic therapy,
photochromics,
prodrugs,
drugs
coating
materials,
chemosensors, non-linear optics, as directing group in catalysis
for C-H functionalizations, and in biotechnology (artificial muscle,
molecular machines, bistable memory devices etc.).
Condensation of aldehydes and amines with azeotropic removal
of water is the traditional approach for the synthesis of imines.[4]
Oxidation of amines is the important transformation to access
various nitrogen containing molecules such as imines, oximes,
amides, nitriles etc.[5] Imines can be obtained by the self
oxidative coupling of amines employing metal catalysts and
oxidants (Scheme 1).[5] Some transition metal-free methods
have also been furnished for the oxidative coupling of amines to
imines[6] such as mesoporus carbon derived from natural vitamin
B12 with molecular oxygen or air,[6i] photooxidative self coupling
of amines using methylene blue,[6j] enzyme mediated oxidation of
benzylamine with H2O2 oxidant,[6k] and also observed in some
extent using K2S2O8 during the oxidation of aliphatic amines to
oximes.[6l] Similarly, vital routes[7] have been developed for the
[a]
Mr. A. D. Hudwekar, Dr. P. K. Verma, Ms. J. Kour, Ms. S. Balgotra,
Dr. S. D. Sawant
Medicinal Chemistry Division
CSIR-Indian Institute of Integrative Medicine
Canal Road, Jammu-180001, India
E-mail: sdsawant@iim.res.in; sdsawant@iiim.ac.in
URL: http://www.iiim.res.in/
[b]
Mr. A. D. Hudwekar, Ms. J. Kour, Ms. S. Balgotra, Dr. S. D. Sawant
Academy of Scientific and Innovative Research (AcSIR)
Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Scheme 1. State of art on synthesis of imines, azobenzenes and present work.
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Results and Discussion
We began our studies using benzyl amine as model substrate
for the optimization of reaction conditions. Initially, reaction was
performed with various additives in ACN, at rt. Reaction
proceeded well in case of TBHP and m-CPBA, however, poor
selectivity was observed (Table 1, entries 1 and 6). Reaction
with H2O2, NaOtBu, KOtBu and H2O get started however, the
conversion and selectivity for the desired product were low
(Table 1, entries 2-5). In case of K2S2O8 high conversion and
selectivity was observed (Table 1, entry 7). Atmospheric oxygen
was also not effective for the reaction (Table 1, entry 8). Hence,
K2S2O8 was selected for further optimization studies. Solvent
plays a critical role for the present reaction. Excellent conversion
was observed in case of H2O, PEG 200, DMSO, DMF and
ethylene glycol, however, best result was observed in PEG 200
(Table 1, entries 9, 11-13 and 15). C2H5OH and 1,4-dioxane
gave the less conversion and selectivity (Table 1, entries 10 and
14).
Figure 1. Optimization of K2S2O8 quantity.
During optimization studies PEG was found to be superior over
other solvents (Table 1). To understand its reason, we have
gone through literature reports and found that PEG have
possibilities of forming half open crown ether type complexes
with potassium ions through self assembling (Scheme 2a) and
also provide stability to the reagent.[9c-9g] To further confirm this
we have carried out controlled reactions for the formation of self
coupled imine and azobenzene in the presence of 18-crown-6
ether instead of PEG 200 as solvent under standard conditions
and found that reaction proceed smoothly with high yields of
product (Scheme 2b and 2c). It indicated that, PEG plays a
critical role for the enhancement of the present reaction,
probably, by promoting the availability of the persulfate anion
and increase the basicity of the reaction.[9c-9g] The possibilities of
any metallic contamination in the PEG were also ruled out by
carrying out its elemental analysis using atomic absorption
spectroscopy.
Table 1. Screening of additives and solvents.[a, d]
Entry
1[c]
2
Additive
TBHP
Solvent
ACN
Con./Sel.[b]
82/19
24/9
H2O2
ACN
3
NaOtBu
KOtBu
H2O
ACN
16/5
4
ACN
11/3
5
ACN
8/7
6
m-CPBA
K2S2O8
Open air
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
ACN
48/17
87/84
13/4
7
ACN
8
ACN
9[c]
10
11
12[c]
13[c]
14
15
H2O
>99/17
63/70
>99/>99
>99/7
>99/54
37/31
82/82
C2H5OH
PEG 200
DMSO
DMF
Scheme 2. Role of PEG 200 in the present reaction.
1,4-Dioxane
Ethylene glycol
With best reaction conditions in hand, the scope of the present
developed protocol was explored for the synthesis of homo
coupled as well as hetero coupled imines (Table 2). Homo
coupling of benzyl amine, -F, -Cl, -CH3, -OCH3 substituted
benzyl amines gave the corresponding imines in excellent yields
(2a-2g). We also thought to inflate the scope of present protocol
for the cross coupling of benzyl amines with other amines. In this
regard, initially, the reaction of equimolar amount of benzyl
amine with aniline gave cross coupled product in 30% yield (2h).
However, on increasing the amount of aniline to 3 equivalents,
the reaction shifts towards desired cross coupled product in 99%
[a] Reaction conditions: benzyl amine (1 mmol), additive (1 equiv.), solvent (5
mL), 12 h, rt. [b] GC conversion and selectivity for imine product.
Benzaldehyde was also observed. [c] Benzaldehyde was formed as major
product. [d] Reactant remains unreacted if not specified.
The quantity of additive, K2S2O8, was also optimized for the
present reaction (Figure 1). 0.5 equiv. of K2S2O8 gave moderate
amount of the desired product, albeit, yield increased upto 92%
with 1 equiv. of additive. However, further increment in the
quantity of K2S2O8 did not increase the reaction yield, rather,
decreased to some extent.
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10.1002/ejoc.201801610
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yield (2i). Reaction of methoxy, methyl and bromo substituted
anilines with benzyl amine and p-methoxybenzyl amine afforded
the corresponding cross coupled imines in excellent yields (2j-
2o). Reaction of benzylamine with p-nitroaniline (strong electron
withdrawing nitro group) could not proceed under present
conditions (results not shown). To our delight, homo coupled
imines were also observed in case of aliphatic amines with
variable chain length (2p-2r). Present protocol was also
applicable for the synthesis of imines in heterocyclic ring
systems (2s and 2t), however, low selectivity was observed in
case of cyclic secondary amines (2u).
observed (4a). Our efforts towards synthesis of unsymmetrical
azo compounds provided three different products under
present conditions i.e., two corresponding symmetrical
products (B and C) from each reactant and one cross coupled
product (A). However, desired unsymmetrical azo compounds
were observed as major product in almost all examples (Table
4). Very high conversion was observed for the reaction of
chloro, bromo, methyl and methoxy substituted anilines with
aniline providing fair selectivities for desired unsymmetrical azo
compounds (5a-5i).
In addition to synthesis of imines and azobenzenes, present
protocol was also applicable for the synthesis of highly valuable
benzothiazoles.[10] Recently, various methods have been
developed for the synthesis of benzothiazoles.[11] Herein, the
reaction of 2-aminothiophenol with different benzylamines
afforded the corresponding 2-arylbenzothiazoles in high yields
(Table 5). Reaction of benzylamine afforded the 2-
phenylbenzothiazole in high yield (6a). Halogens (Cl, CF3),
methyl, and methoxy functional groups were tolerated under
the present conditions (6b-6e). Reaction of 4-pyridinylamine
and naphthylamine gave the desired benzothiazoles in high
yields (6f, 6g).
Table 2. Synthesis of symmetrical and unsymmetrical imines via oxidative
coupling of amines.
homo coupling of benzylamines[a, d]
2a, R = H; 99% (82%)
N
2b, R = m-F; 99% (76%)
R
R
2c, R = p-F; 99%
2d, R = m-Cl; 94% (79%)
2e, R = p-CH3; 99% (81%)
2f, R = m-OCH3; 91%
2g, R = p-OCH3; 99%
cross coupling of benzylamines with anilines[b, d]
2h, R, R1 = H; 30%[e, f]
Table 3. Synthesis of symmetrical azoarenes.[a, b]
2i, R, R1 = H; 99%
N
R1
R
2j, R = o-CH3, o'-CH3, R1=H; 99%
2k, R = m-CH3, m'-CH3, R1= H; 99%
2l, R = o-CH3, m-CH3, R1= H; 99%
2m, R = p-OCH3, R1= H; 99%
2n, R= p-CH3, R1= p-OCH3; 99%
2o, R= p-Br, R1= p-OCH3; 75%
homo coupling of aliphatic amines[c, d]
2p, R = CH3, n = 3; 99%
2q, R = CH3, n = 4; 99%
2r, R = CH3, n = 5; 99%
R
R
n
N
n
imine formation in heteroaromatic substrates[a, d]
Y
Y
N
N
2u, 64%[g]
2s, y = S, 99%; 2t, y = O, 99%
[a] Reaction conditions: amine (1 mmol), K2S2O8 (1 equiv.), PEG 200 (5 mL),
12 h, rt. [b] Reaction conditions: benzyl amine (1 mmol), amine (3 equiv.),
K2S2O8 (1 equiv.), PEG 200 (5 mL), 12 h, rt. Yields based on benzyl amine.
[c] Reaction conditions: amine (1 mmol), K2S2O8 (1 equiv.), PEG 200 (5 mL),
12 h, rt. [d] GC yields (isolated yields in parentheses). [e] Reaction with 1
equiv. of aniline. [f] Benzaldehyde and homo coupled azobenzene were also
observed. [g] 20% of isoquinoline was also observed.
After the synthesis of imines, next we successfully applied the
developed protocol for the synthesis of symmetrical and
unsymmetrical aromatic azo compounds, with additional
requirement of inexpensive and easily available base, K2CO3
(Table 3 and 4). The reaction of methyl, methoxy, halides (Cl,
Br), trifluoromethoxy, dimethyl, dimethoxy and unsubstituted
anilines afforded the corresponding symmetrical azo
compounds in good to excellent yields (4a-4e and 4g-4j).
Albeit, 3-fluoroaniline (4f) and 4-(trifluoromethyl)aniline (4k)
gave the corresponding product in very low yields and remains
unreacted under present conditions. The gram scale
applicability of the method was also tested by carrying out the
reaction of aniline at 5g scale, slightly low yield of product was
[a] Reaction conditions: amine (1 mmol), K2S2O8 (1 equiv.), K2CO3 (1 equiv.)
PEG 200 (5 mL), 12 h, rt. [b] Isolated Yields. [c] Reactant remains unreacted.
[d] GC Yield. [e] Reaction at 5 g scale in parenthesis
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10.1002/ejoc.201801610
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Table 4. Synthesis of unsymmetrical azoarenes.[a]
Table 5. Synthesis of benzothiazoles.[a, b]
[a] Reaction conditions: 2-aminothiophenol (1 mmol), amine (1 mmol),
K2S2O8 (1 equiv.), K2CO3 (1 equiv.), PEG 200 (5 mL), 12 h, rt. [b] Isolated
yields.
Table 6. Synthesis of disulfides.[a, b]
[a] Reaction conditions: amine (1 mmol), aniline (1 mmol), K2S2O8 (1 equiv.),
K2CO3 (1 equiv.), PEG 200 (5 mL), 12 h, rt. [b] GC based conversion and
selectivity (isolated yields in parentheses).
Disulfides belong to biologically important class of molecules, as
reported in literature.[12] As an extension of the current method,
disulfides were also prepared using current protocol from
thiophenols under optimized conditions in excellent yields (Table
6). Reaction of unsubstituted, methyl, methoxy and amine
substituted thiophenols afforded the corresponding disulfide
products in high yields (7a-7c and 7e). Reactions with thiol
bearing activated methylene moiety in aromatic as well as
heteroaromatic compound also gave the desired disulfide in high
yields (7d and 7f). Reaction of aliphatic cyclic and acyclic thiols
have also afforded the corresponding disulfides in good yields
(7g and 7h). Interestingly, the reaction of 4-methylthiophenol
with 4-methoxythiophenol gave the cross coupled disulfide as
the major product in good yield (7i), which gives scope for
generating diverse asymmetric disulfides.
[a] Reaction conditions: thiophenol (1 mmol), K2S2O8 (1 equiv.), K2CO3 (1
equiv.), amine (1 mmol), PEG 200 (5 mL), 12 h, rt. [b] GC yields (Isolated
yields in parentheses).
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desired azo compounds (i). During GC-MS analysis of reaction
mixtures, the diphenyl hydrazine intermediate (h) was also
observed in some cases. Similarly, persulfate anion promotes
the synthesis of disulfides (k) from thiophenols (j) via abstraction
of protons. For the synthesis of benzothiazoles (o), the in situ
oxidation
of
benzylamine
to
benzaldehyde/imine
formation/cyclization/oxidation pathway was followed.[14,
K2S2O8 promoted the formation of benzaldehyde (e) which
immediately form imines (m), which remain in equilibrium with
the cyclized product (n),[14, 11g] which is then oxidized either by
K2S2O8 or oxygen[15] to the desired benzothiazoles (o).
11g]
Conclusions
In summary, we have developed an efficient, environment
friendly, transition metal-free protocol for the synthesis of imines
and azobenzenes using PEG 200 as biocompatible and green
reaction solvent at room temperature. Present protocol is
applicable to the synthesis of symmetrical as well as
unsymmetrical imines and azobenzenes from primary amines.
Diverse functional groups were well tolerated under the
developed conditions and yielding the desired product in high
selectivities and yields. Present protocol was also applicable for
the synthesis of highly valuable benzothiazoles and disulfides.
Present method provide an effective alternative to the existing
transition metal based methodologies to access highly valuable
intermediate stage molecules which can be further utilized in
numerous fields.
Experimental Section
Scheme 3. Proposed reaction pathways.
General Information: All solvents were purified and dried as per
standard protocols. All reagents were obtained from commercial sources
and used without purification. 1H NMR spectra were obtained at 400 MHz
On the basis of observed results and earlier developed
11g, 11h, 11n, 16]
the mechanistic pathways for
or 500 MHz and recorded relative to tetramethylsilane signal (0 ppm). 13
C
methodologies[5e,
NMR spectra were obtained at 100 MHz or 125 MHz and chemical shifts
were recorded relative to the CDCl3 (77.0 ppm). Data for 1H NMR are
recorded as follows, chemical shift (δ, ppm). Multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet, br = broad singlet, coupling constant(s)
in Hz, integration). Data for 13C NMR were reported in terms of chemical
shift (δ, ppm). The HRMS spectra were recorded on Agilent 6540 Ultra-
High-Definition (UHD) Accurate-Mass Quadrupole Time-of-Flight (Q-
TOF) liquid chromatography/mass spectrometry (LC/MS) system. GC-
MS analysis was performed on a VARIAN GC-MS-MS instrument.
present protocols are illustrated in Scheme 3. Benzyl amine gets
converted into peroxide intermediate[11n, 16] (b) by K2S2O8 which
subsequently transformed into imine intermediate (c) with the
removal of H2O2. After the formation of imine intermediate (c),
two different paths (x and y)[5e] are known for the imine (f)
formation. In path (x), the intermolecular nucleophilic attack of
benzyl amine (a) on the imine (c) intermediate gave N-alkylated
diamine intermediate (d), which is converted into desired imine
(f) product with the removal of ammonia. Alternatively, in path (y),
the imine intermediate (c) get converted into aldehyde (e), which
on condensation either with imine (c) or benzyl amine (a)
molecule provide the desired imine (f) product. The observation
of aldehydes as byproduct during some of the reactions
indicated the path (y) for the present protocol, although, the
possibilities of path (x) cannot be ruled out under the present
conditions. Preferentially, for the synthesis of azobenzenes, the
well established direct route for the oxidation of anilines (g) to
nitro compounds[13] was followed and under the conditions the
reaction get stopped at the intermediate stage to give the
General procedure for synthesis of homo coupled imines: A dry
round bottom flask (25 mL) was charged with benzyl amine (1 mmol),
K2S2O8 (1 equiv.) in PEG 200 (5 mL) at room temperature and stirred for
12 h. After completion (monitored by TLC), the reaction mixture was
dissolved in a mixture of ethyl acetate: n-hexane (30:70) and washed
with H2O (3 times). The organic phases were combined and concentrated
on rotary evaporator. The crude residue was analyzed by GC or purified
using Silica gel (ethyl acetate: n-hexane) to give the desired product.
General procedure for synthesis of cross coupled imines: A dry
round bottom flask (25 mL) was charged with benzyl amine (1 mmol),
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other amine (3 equiv.), K2S2O8 (1 equiv.) in PEG 200 (5 mL) at room
temperature and stirred for 12 h. After completion (monitored by TLC),
the reaction mixture was dissolved in a mixture of ethyl acetate: n-
hexane (30:70) and washed with H2O (3 times). The organic phases
were combined and concentrated on rotary evaporator. The crude
residue was analyzed by GC.
Table 2, Entry 2h and 2i:[11g] EI-MS (m/z): 180.2 [M]+, 104, 77, 50.
Table 2, Entry 2j:[20] EI-MS (m/z): 209.3 [M]+, 194, 165, 132, 117, 77, 51.
Table 2, Entry 2k:[21] EI-MS (m/z): 209.3 [M]+, 132, 105, 77, 51.
Table 2, Entry 2l:[11g] EI-MS (m/z): 210.3 [M]+, 132, 103, 77.
Table 2, Entry 2m:[6b] EI-MS (m/z): 211 [M]+, 196, 167, 141, 115, 89, 63.
Table 2, Entry 2n:[22] EI-MS (m/z): 225 [M]+, 207, 181, 91, 65.
Table 2, Entry 2o:[22] EI-MS (m/z): 289 [M]+, 253, 207, 156, 76.
Table 2, Entry 2p:[23] EI-MS (m/z): 156.2 [M]+, 126, 112, 98, 84, 70, 56,
41.
Table 2, Entry 2q:[17] EI-MS (m/z): 184.5 [M]+, 140, 112, 84, 70, 41.
Table 2, Entry 2r:[24] EI-MS (m/z): 212.4 [M]+, 154, 126, 98, 70, 41.
Table 2, Entry 2s:[17] EI-MS (m/z): 207.4 [M]+, 123, 97, 69, 45.
Table 2, Entry 2t:[25] EI-MS (m/z): 175.1 [M]+, 147, 118, 94, 81, 53.
Table 2, Entry 2u:[25] EI-MS (m/z): 130.3 [M]+, 103, 78, 51.
Table 3, Entry 4a:[26] Red solid; 1HNMR (400 MHz, CDCl3): δ = 8.03 (d, J
= 8Hz, 4H), 7.57 (m, 6H); 13C (126 MHz, CDCl3): δ = 152.7, 131.1, 129.2,
123.0; HRMS (ESI) m/z: calcd. for C12H11N2 [M+H]+ 183.0922; found:
183.0911.
Table 3, Entry 4b:[26] Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.83 (d,
J = 8Hz, 4H), 7.32 (d, J = 8Hz, 4H), 2.44 (s, 6H); 13C (126 MHz, CDCl3):
δ = 150.8, 141.2, 129.7, 122.7, 21.4; HRMS (ESI) m/z: calcd. for
C14H14N2Na [M+Na]+ 233.1055; found: 233.1066.
Table 3, Entry 4c:[26] Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.83 (d,
J = 8Hz, 4H), 7.32 (d, J = 8Hz, 4H), 2.44 (s, 6H); 13C (126 MHz, CDCl3):
δ = 150.8, 141.2, 129.7, 122.7, 21.4; HRMS (ESI) m/z: calcd. for
C14H15N2O2 [M+H]+ 243.1134; found: 243.1126.
General procedure for synthesis of symmetrical azobenzenes: A dry
round bottom flask (25 mL) was charged with amine (1 mmol), K2S2O8 (1
equiv.), K2CO3 (1 equiv.) in PEG 200 (5 mL) at room temperature and
stirred for 12 h. After completion (monitored by TLC), the reaction mixture
was dissolved in a mixture of ethyl acetate: n-hexane (30:70) and
washed with H2O (3 times). The organic phases were combined and
concentrated on rotary evaporator. The crude residue was analyzed by
GC or purified using Silica gel (ethyl acetate: n-hexane) to give the
desired product.
General procedure for synthesis of unsymmetrical azobenzenes: A
dry round bottom flask (25 mL) was charged with aniline (1 mmol), other
amine (1 mmol), K2S2O8 (1 equiv.), K2CO3 (1 equiv.) in PEG 200 (5 mL)
at room temperature and stirred for 12 h. After completion (monitored by
TLC), the reaction mixture was dissolved in a mixture of ethyl acetate: n-
hexane (30:70) and washed with H2O (3 times). The organic phases
were combined and concentrated on rotary evaporator. The crude
residue was analyzed by GC or purified using Silica gel (ethyl acetate: n-
hexane) to give the desired product.
General procedure for synthesis of benzothiazoles: A dry round
bottom flask (25 mL) was charged with 2-aminothiophenol (1 mmol),
amine (1 mmol), K2S2O8 (1 equiv.), K2CO3 (1 equiv.) in PEG 200 (5 mL)
at room temperature and stirred for 12 h. After completion (monitored by
TLC), the reaction mixture was dissolved in a mixture of ethyl acetate: n-
hexane (30:70) and washed with H2O (3 times). The organic phases
were combined, concentrated on rotary evaporator and purified using
Silica gel (ethyl acetate: n-hexane) to give the desired product.
General procedure for synthesis of disulfides: A dry round bottom
flask (25 mL) was charged with thiophenols (1 mmol), K2S2O8 (1 equiv.),
K2CO3 (1 equiv.) in PEG 200 (5 mL) at room temperature and stirred for
12 h. After completion (monitored by TLC), the reaction mixture was
dissolved in a mixture of ethyl acetate: n-hexane (30:70) and washed
with H2O (3 times). The organic phases were combined, concentrated on
rotary evaporator. The crude residue was analyzed by GC or purified
using Silica gel (ethyl acetate: n-hexane) to give the desired product.
Spectral Data
Table 2, Entry 2a:[17] Yellow liquid; 1HNMR (400 MHz, CDCl3): δ = 8.43
(s, 1H), 7.80-7.83 (m, 2H), 7.49-7.50 (m, 2H), 7.44-7.46 (m, 3H), 7.37-
7.38 (m, 3H), 4.86 (s, 2H); EI-MS (m/z): 195.3 [M]+, 117, 91, 65, 51.
Table 2, Entry 2b:[18] Yellow liquid; 1HNMR (400 MHz, CDCl3): δ = 8.40
(s, 1H), 7.54-7.59 (m, 2H), 7.40-7.45 (m, 1H), 7.31-7.35 (m, 1H), 7.14-
7.19 (m, 2H), 7.08-7.10 (m, 1H), 6.97-7.01 (m, 1H), 4.84 (s, 2H); EI-MS
(m/z): 231.4 [M]+, 135, 109, 83, 75.
Table 3, Entry 4d:[27] Red solid; 1HNMR (400 MHz, CDCl3): δ = 7.80 (m,
4H), 7.66 (m, 4H); 13C (126 MHz, CDCl3): δ = 151.1, 132.4, 125.7, 124.4;
HRMS (ESI) m/z: calcd. for
C
12H9N2Br2 [M+H]+ 340.9112; found:
340.9101.
Table 3, Entry 4e:[27] Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.87 (d,
J = 8Hz, 4H), 7.49 (d, J = 8Hz, 4H); 13C (126 MHz, CDCl3): δ = 150.8,
137.2, 129.4, 124.2; HRMS (ESI) m/z: calcd. for C12H9N2Cl2 [M+H]+
251.0143; found: 251.0122.
Table 3, Entry 4f:[7i] Red solid; 1HNMR (400 MHz, CDCl3): δ = 7.87 (d, J
= 8Hz, 4H), 7.49 (d, J = 8Hz, 4H); 13C (126 MHz, CDCl3): δ = 164.2,
162.3, 153.8, 153.7, 130.3, 130.3, 120.8, 120.8, 118.3, 118.1, 108.2,
108.0; HRMS (ESI) m/z: calcd. for C12H9N2F2 [M+H]+ 219.0734; found:
219.0717.
Table 3, Entry 4g:[28] Red solid; 1HNMR (400 MHz, CDCl3): δ = 7.97 (m,
4H), 7.36 (d, J = 8Hz, 4H); 13C (126 MHz, CDCl3): δ = 151.1, 150.4,
124.4, 121.2; HRMS (ESI) m/z: calcd. for C14H9F6N2O2 [M+H]+ 351.0568;
found: 350.0561.
Table 3, Entry 4h:[26] Orange solid; 1HNMR (400 MHz, CDCl3): δ = 7.69
(s, 2H), 7.66 (d, J = 8Hz, 2H), 7.27 (d, J = 8Hz, 2H), 2.36 (s, 6H), 2.34, (s,
6H); 13C (126 MHz, CDCl3): δ = 151.2, 139.8, 137.3, 130.2, 123.3, 120.7,
19.8, 19.8; HRMS (ESI) m/z: calcd. for C16H19N2 [M+H]+ 239.1548; found:
239.1554.
Table 2, Entry 2c:[17] EI-MS (m/z): 231.3 [M]+, 183, 135, 109, 83, 76, 57.
Table 2, Entry 2d:[19] Yellow liquid; 1HNMR (400 MHz, CDCl3): δ = 8.37
(s, 1H), 7.84 (s, 1H), 7.65-7.67 (m, 1H), 7.36-7.45 (m, 3H), 7.24-7.31 (m,
4H, mixed with solvent signal), 4.82 (s, 2H); EI-MS (m/z): 263.4 [M]+, 228,
151, 125, 99, 89, 75.
Table 2, Entry 2e:[17] White solid; 1HNMR (400 MHz, CDCl3): δ = 8.37 (s,
1H), 7.68-7.70 (m, 2H), 7.22-7.25 (m, 4H), 7.16-7.18 (m, 2H), 4.79 (s,
2H), 2.41 (s, 3H), 2.36 (s, 3H); EI-MS (m/z): 223.4 [M]+, 165, 131, 105,
89, 77, 65.
Table 3, Entry 4i:[27] Orange solid; 1HNMR (400 MHz, CDCl3): δ = 7.55 (s,
4H), 7.13 (s, 2H), 2.34, (s, 12H); 13C (126 MHz, CDCl3): δ = 152.9, 138.7,
132.5, 120.5, 21.2; HRMS (ESI) m/z: calcd. for C16H19N2 [M+H]+
239.1548; found: 239.1529.
Table 3, Entry 4j: Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.13 (d, J
= 5Hz, 4H), 6.61 (t, J = 5Hz, 2H), 3.88, (s, 12H); 13C (126 MHz, CDCl3): δ
=
161.1, 154.3, 104.0, 100.9, 55.6; HRMS (ESI) m/z: calcd. for
C16H19N2O2 [M+H]+ 303.1345; found: 303.1344.
Table 3, Entry 4k:[7i] EI-MS (m/z): 318.10 [M]+, 144.90, 95.14.
Table 4, Entry 5a:[29]
Table 2, Entry 2f:[3] EI-MS (m/z): 255.3 [M]+, 224, 132, 122, 107, 91, 78,
51.
Table 2, Entry 2g:[17] EI-MS (m/z): 255.4 [M]+, 147, 132, 121, 77, 51.
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10.1002/ejoc.201801610
European Journal of Organic Chemistry
FULL PAPER
A: 1H NMR (400 MHz, CDCl3): δ = 8.37 – 8.28 (m, 1H), 8.21 (dd, J = 8.4,
7.2 Hz, 2H), 8.12 (dd, J = 9.2, 2.2 Hz, 1H), 7.70 – 7.39 (m, 5H); EI-MS
(m/z): 260.4 [M]+, 183, 155, 105, 77, 51.
126.3, 125.2, 123.2, 121.6; HRMS (ESI) m/z: calcd. for C13H9NS [M+H]+
212.0534, found 212.0525.
Table 5, Entry 6b:[34] White solid; 1H NMR (400 MHz, CDCl3): δ = 8.06
(m, 3H), 7.90 (d, J = 7Hz, 1H), 7.49 (m, 3H), 7.40 (m, 1H); 13C NMR (101
MHz, CDCl3): δ = 166.6, 154.0, 137.0, 135.0, 132.1, 129.3, 128.7, 126.5,
125.4, 123.3, 121.6; HRMS (ESI) m/z: calcd. for C13H8NSCl [M+H]+
246.0144, found 246.0133.
Table 5, Entry 6c:[21] Pale yellow solid; 1H NMR (400 MHz, CDCl3): δ =
8.07 (m, 3H), 7.87 (d, J = 7Hz, 1H), 7.50 (m, 1H), 7.37 (m, 1H), 7.02 (m,
2H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3): δ = 167.8, 161.9, 154.2,
134.9, 129.1, 126.4, 126.2, 124.8, 122.8, 121.5, 114.3, 55.4; HRMS (ESI)
m/z: calcd. for C14NSO [M+H]+ 242.0640, found 242.0636.
B: 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.9 Hz, 2H), 8.13 – 8.07 (m,
2H), 7.70 – 7.60 (m, 4H).
C: 1H NMR (400 MHz, CDCl3): δ = 8.42 – 8.30 (m, 2H), 8.21 (dd, J = 8.5,
0.9 Hz, 2H), 7.61 – 7.49 (m, 5H), 7.43 (dd, J = 8.3, 6.5 Hz, 1H).
Table 4, Entry 5b:[29]
A: 1H NMR (400 MHz, CDCl3): δ = 8.39 – 8.30 (m, 2H), 8.25 – 8.16 (m,
2H), 7.66 – 7.49 (m, 4H), 7.43 (dd, J = 8.3, 6.4 Hz, 1H); EI-MS (m/z):
216.3 [M]+, 139, 111, 77, 51.
B: 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.7 Hz, 2H), 8.19 (d, J =
8.7 Hz, 2H), 7.49 (dd, J = 13.0, 8.8 Hz, 4H).
C: 1H NMR (400 MHz, CDCl3): δ = 8.31 (t, J = 8.4 Hz, 2H), 8.26 – 8.16
(m, 2H), 7.70 – 7.39 (m, 6H).
Table 5, Entry 6d:[35] Pale yellow solid; 1H NMR (400 MHz, CDCl3): δ =
8.20(d, J = 7Hz, 2H), 8.11 (d, J = 7Hz, 1H), 7.93 (d, J = 7Hz, 1H), 7.75 (d,
J = 7Hz, 2H), 7.53 (t, J = 7Hz, 1H), 7.43 (t, J = 7Hz, 1H); 13C NMR (101
MHz, CDCl3): δ = 154.0, 150.8, 140.5, 135.2, 126.8, 126.2, 123.9, 121.8,
121.2; HRMS (ESI) m/z: calcd. for C14H8F3NS [M+H]+ 280.0408, found
280.0401.
Table 5, Entry 6e:[34] White crystal; 1H NMR (400 MHz, CDCl3): δ = 8.13
(d, J = 7Hz, 1H), 8.00 (s, 1H), 7.90 (t, J = 7Hz, 2H), 7.53 (m, 1H), 7.40 (t,
J = 7Hz, 2H), 7.32 (d, J = 7Hz, 1H), 2.48 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ = 168.3, 154.2, 138.8, 135.1, 133.5, 131.8, 128.9, 128.0, 126.3,
125.1, 124.9, 123.2, 121.6, 21.4; HRMS (ESI) m/z: calcd. for C14H11NS
[M+H]+ 226.0690, found 226.0685.
Table 4, Entry 5c:[29]
A: Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8Hz, 2H),
7.88 (d, J = 8Hz, 2H), 7.50 (m, 2H), 7.44 (m, 1H), 7.03 (m, 2H), 3.90 (s,
3H); 13C (126 MHz, CDCl3): δ = 162.0, 152.7, 147.0, 130.3, 129.0, 124.7,
122.5, 114.2, 55.6; HRMS (ESI) m/z: calcd. for C14H15N2O2 [M+H]+
213.1028; found: 213.0997; EI-MS (m/z): 212.2 [M]+, 135, 115, 107, 92,
77, 51.
B: EI-MS (m/z): 242.2 [M]+, 135, 107, 92, 77, 64.
C: EI-MS (m/z): 182.2 [M]+, 152, 105, 77, 51.
Table 4, Entry 5d:[30] EI-MS (m/z): 210.5 [M]+, 165, 133, 105, 77, 51.
Table 4, Entry 5e:[31] EI-MS (m/z): 210.4 [M]+, 194, 165, 133, 105, 77, 51.
Table 4, Entry 5f:
A: Red solid; 1HNMR (400 MHz, CDCl3): δ = 7.94 (m, 2H), 7.52 (m, 3H),
7.17 (d, J = 8Hz, 2H), 6.63 (t, J = 4Hz, 1H), 3.88 (s, 6H); 13C (126 MHz,
CDCl3): δ = 161.1, 154.4, 152.5, 131.1, 129.1, 122.9, 103.9, 100.9, 55.6;
HRMS (ESI) m/z: calcd. forC14H15N2O2 [M+H]+ 243.1134; found:
243.1078; EI-MS (m/z): 242.4 [M]+, 214, 137, 122, 105, 77, 51;
C: EI-MS (m/z): 182.2 [M]+, 152, 105, 77, 51.
Table 5, Entry 6f:[35] Off white solid; 1H NMR (400 MHz, CDCl3): δ = 8.78
(d, J = 7Hz, 2H), 8.14 (d, J = 7Hz, 1H), 7.96 (m, 3H), 7.56 (m, 1H), 7.48
(m, 1H); 13C NMR (101 MHz, CDCl3): δ = 165.1, 153.9, 150.7, 140.4,
135.2, 126.8, 126.2, 123.9, 121.9, 121.2; HRMS (ESI): calcd. for
C12H9N2S ([M+H]+ 213.0480, found 213.0480.
Table 5, Entry 6g:[36] Pale yellow solid; 1H NMR (400 MHz, CDCl3): δ =
8.55 (s, 1H), 8.20 (m, 1H), 8.14 (m, 1H), 7.90 (m, 4H), 7.53 (m, 3H), 7.39
(m, 1H); 13C NMR (101 MHz, CDCl3): δ = 168.1, 154.2, 135.1, 134.6,
133.1, 130.9, 128.3, 128.8, 127.9, 127.6, 127.5, 126.9, 126.4, 125.2,
124.4, 123.2, 121.7; HRMS (ESI) m/z: calcd. for C17H11NS [M+H]+
262.0690, found 262.0685.
Table 6, Entry 7a:[26] White solid; 1HNMR (400 MHz, CDCl3): δ = 7.58 (d,
J = 8Hz, 4H), 7.35 (m, 4H), 7.28 (m, 2H); 13C (126 MHz, CDCl3): δ =
137.2, 129.2, 127.7, 127.3; EI-MS (m/z): 218.2 [M]+, 185, 154, 109, 65.
Table 6, Entry 7b:[26] White solid; 1HNMR (400 MHz, CDCl3): δ = 7.54 (d,
J = 8Hz, 4H), 7.23 (d, J = 8Hz, 4H), 2.45 (s, 6H); 13C (126 MHz, CDCl3):
δ = 137.5, 134.1, 130.0, 128.7, 21.2; EI-MS (m/z): 246.2 [M]+, 213, 182,
167, 123, 91, 79, 45.
Table 4, Entry 5g:[29]
A: Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.91 (m, 2H), 7.79 (d, J =
8Hz, 2H), 7.30 (d, J = 8Hz, 2H), 7.01 (m, 2H), 3.89 (s, 3H), 2.43 (s, 3H);
13C (126 MHz, CDCl3): δ = 161.8, 150.8, 147.0, 140.8, 129.7, 124.5,
122.5, 114.1, 55.5, 21.4; HRMS (ESI) m/z: calcd. for C14H15N2O [M+H]+
227.1184; found: 227.1169; EI-MS (m/z): 226.4 [M]+, 214, 135, 107, 91,
77, 64.
B: EI-MS (m/z): 242.2 [M]+, 135, 107, 92, 77, 64.
C: EI-MS (m/z): 210.0 [M]+, 166, 119, 91, 65.
Table 4, Entry 5h:[32]
Table 6, Entry 7c:[26] Off white solid; 1HNMR (400 MHz, CDCl3): δ = 7.41
(d, J = 8Hz, 4H), 7.12 (d, J = 8Hz, 4H), 2.34 (s, 6H); 13C (126 MHz,
CDCl3): δ = 137.4, 134.0, 129.8, 128.6, 21.0; EI-MS (m/z): 278.3 [M]+,
246, 139, 96, 70.
Table 6, Entry 7d:[26] White solid; 1HNMR (400 MHz, CDCl3): δ = 7.40 (m,
10H), 3.71 (s, 4H); 13C (126 MHz, CDCl3): δ = 137.5, 129.6, 128.6, 127.6,
43.4; EI-MS (m/z): 246.1 [M]+, 181, 121, 91, 65.
A: Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.91 (m, 2H), 7.76 (m,
2H), 7.63 (m, 2H), 7.02 (m, 2H), 3.90 (s, 3H); 13C (126 MHz, CDCl3): δ =
162.3, 151.5, 146.8, 132.4, 132.2, 124.9, 124.1, 114.3, 55.6; HRMS (ESI)
m/z: calcd. for C13H12N2OBr [M+H]+ 291.0133; found: 291.0099; EI-MS
(m/z): 290 [M]+, 242, 156, 135, 107, 77.
C: EI-MS (m/z): 338 [M]+, 281, 207, 177, 81.
Table 4, Entry 5i:[33]
Table 6, Entry 7e:[26] Pale yellow solid; 1HNMR (400 MHz, CDCl3): δ =
7.18 (d, J = 4Hz, 4H), 6.71 (d, J = 8Hz, 2H), 6.60 (s, 2H), 4.34 (s, 4H);
13C (126 MHz, CDCl3): δ = 148.6, 136.8, 131.6, 118.7, 118.2, 115.2; EI-
MS (m/z): 248.0 [M]+, 207, 124, 71.
Table 6, Entry 7f:[26] Brown solid; 1HNMR (400 MHz, CDCl3): δ = 7.40 (m,
2H), 6.34 (m, 2H), 6.24 (d, J = 4Hz, 2H), 3.70 (s, 4H); 13C (126 MHz,
CDCl3): δ = 150.2, 142.5, 110.8, 109.0, 35.6; EI-MS (m/z): 226.02[M]+,
161, 81, 53.
A: Yellow solid; 1HNMR (400 MHz, CDCl3): δ = 7.91 (m, 2H), 7.83 (m,
2H), 7.47 (m, 2H), 7.02 (m, 2H), 3.90 (s, 3H); 13C (126 MHz, CDCl3): δ =
162.3, 151.1, 146.8, 136.1, 129.2, 124.8, 123.8, 114.2, 55.6; HRMS (ESI)
m/z: calcd. for C13H12N2OCl [M+H]+ 247.0638; found: 247.0644. EI-MS
(m/z): 246.0 [M]+, 207, 135, 107, 75.
B: EI-MS (m/z): 242.2 [M]+, 135, 107, 92, 77, 64.
C: EI-MS (m/z): 250.0 [M]+, 207, 152, 139, 111, 75.
Table 5, Entry 6a:[34] Off white solid; 1H NMR (400 MHz, CDCl3): δ =
8.10 (m, 3H), 7.90 (d, J = 7Hz, 1H), 7.50 (m, 4H), 7.39 (m, 1H); 13C NMR
(101 MHz, CDCl3): δ = 168.0, 154.2, 135.1, 133.6, 130.9, 129.0, 127.6,
Table 6, Entry 7g:[26] White solid; 1HNMR (400 MHz, CDCl3): δ = 2.68-
2.71 (m, 2H), 2.03-2.05 (m, 4H), 1.77-1.79 (m, 4H), 1.60-1.63 (m, 2H),
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10.1002/ejoc.201801610
European Journal of Organic Chemistry
FULL PAPER
1.25-1.34 (m, 10H); 13C (126 MHz, CDCl3): δ = 49.9, 32.8, 26.1, 25.7; EI-
MS (m/z): 230.10 [M]+, 148, 83.10.
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[4]
[5]
Table 6, Entry 7h:[26] White solid; 1HNMR (400 MHz, CDCl3): δ = 2.69 (t,
J = 8Hz, 4H), 1.66 (m, 4H), 1.42 (m, 4H), 0.97 (t, J = 7Hz, 6H); 13C (126
MHz, CDCl3): δ = 38.8, 31.3, 21.6, 13.6; EI-MS (m/z): 178.00 [M]+, 122,
88, 57.
Table 6, Entry 7i: Off-white solid; 1H NMR (400 MHz, CDCl3): δ = 7.75 –
7.36 (m, 4H), 7.18 (dd, J = 7.6, 5.3 Hz, 2H), 7.07 – 6.74 (m, 2H), 3.84 (d,
J = 5.2 Hz, 3H), 2.40 (d, J = 4.9 Hz, 3H); EI-MS (m/z): 262.10 [M]+, 229.9,
171, 139, 95.
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Acknowledgements
The funding support from CSIR-India funded project HCP0008
and BSC0108 is gratefully acknowledged. PKV is thankful to
DST-SERB for the Fast-track Young Scientist Grant. SDS
thanks CSIR for the award of Raman Research Fellowship. IIIM
communication No. IIIM/2262/2018.
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[6]
Keywords: amines • oxidation • azo compounds • imines •
disulfides
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Abhinandan D. Hudwekar, Praveen
Kumar Verma, Jaspreet Kour, Shilpi
Balgotra, Sanghapal D. Sawant*
Key Topic: Oxidation of Amines
Page No. – Page No.
Transition
Coupling of Primary Amines in
Polyethylene Glycol at Room
Metal-Free
Oxidative
Temperature: Synthesis of Imines,
Azobenzenes, Benzothiazoles and
Disulfides
A transition metal-free protocol has been developed for the oxidative coupling of
primary amines to imines and azobenzenes, thiols to disulfides and 2-
aminothiophenols to benzothiazoles offering excellent yields. The advantageous
features of the present environmentally benign methodology includes the usage of
biocompatable and green reaction conditions like solvent, room temperature
reactions, transition metal-free approach and moreover, it offers broader substrate
scope.
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