Ionic liquid catalysed aerobic oxidative amidation and thioamidation of benzylic amines under neat conditions

Article abstract of DOI:10.1039/c8gc03726d

Tetrabutylammonium hydroxide (TBAOH) was discovered as a highly efficient and green catalyst for aerobic oxidation of the α-methylene carbon of primary amines as well as benzylic groups into the corresponding amides and ketones under neat conditions. We described herein, ionic liquid TBAOH catalysed aerobic oxidation of benzyl amines to benzamides and with elemental sulfur; the corresponding benzylbenzothioamides were obtained under metal-free, oxidant-free and base-free conditions. Applicability at the gram scale for the synthesis of the desired amides/ketones is also demonstrated with the present protocol.

Full text of DOI:10.1039/c8gc03726d

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DOI: 10.1039/C8GC03726D
Green Chemistry
COMMUNICATION
Ionic Liquid Catalysed Aerobic Oxidative Amidation and
Thioamidation of Benzylic Amines under Neat Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Abhisek Joshi, Rahul Kumar, Rashmi Semwal, Deepa Rawat and Subbarayappa Adimurthy*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tetrabutylammonium hydroxide TBAOH was discovered as a development of novel and green methods for amide synthesis
highly efficient and green catalyst for aerobic oxidation of α- is highly desirable.
methylene carbon of primary amines as well as benzylic groups Recent methods on the synthesis of amides are being focused
into corresponding amides and ketones under neat conditions. We on the direct oxidation of primary amines to corresponding
described herein, ionic liquid TBAOH catalysed aerobic oxidation amides.6 Most of the reported methods demand the
of benzyl amines to benzamides and with elemental sulfur the requirement of either expensive metal complexes or
corresponding benzylbenzothioamides were obtained under stoichiometric oxidants such as iodine, RuO4, tBuOOH,
t
metal-free, oxidant-free and base-free conditions. Applicability at iodosobenzene and PhCO3 Bu.7,8 In contrast to the transition-
gram scale synthesis of desired amides/ketones are also
demonstrated with the present protocol.
Jana and Talbot Group
O
H
H
R
Amides are the most important class of compounds in
chemistry as well as in biology due to their wider utility as
intermediates in the organic chemistry1 and also in proteins
and peptide synthesis. Amides are also used widely in polymer
industry.2 Recently, amides have been employed in many
cross-coupling reactions through C—N bond cleavage.3
Traditionally amides have been prepared by the reaction of
carboxylic acid derivatives such as esters, acid anhydrides and
acid chlorides with amines.4 Hydration of nitriles5 and the
Beckmann rearrangement have been practically useful in the
production of large-scale industrial chemicals. However, these
methods require stoichiometric amounts of toxic/hazardous
reagents and ultimately, they generate large amount of waste
chemicals or by-products. Many instances, it requires careful
handling of expensive metal complexes and ligands. Over the
past decade, chemists have made great efforts to develop
suitable and environmentally friendly processes, and in this
context, the development of new methodologies for amide
bond formation represents a major challenge for chemical
industries and for academic research groups. Therefore, the
R
more than stoichiometric
amount of reagents were used
NH
R'
NH
R'
primary, secondary
and cyclic amines
Our previous work
O
H
I2-TBHP
H
R1
R1
10 equiv. of TBHP was used
R
N
R
N
H
H
R= aryl, naphthyl
R1= H, Me, Et, Ph etc...
This work
S
O
S8
N
Ar/
Het
Ar/
Het
O2(air)
NH2
Ar/
Het
NH2
H
Ar/
Het
Ionic liquid
Ionic Liquid
Metal free
Oxidant free
Base free
Solvent free
Scheme 1: Metal-free synthesis of amides
metal catalysts, metal-free approaches which employ aerobic
oxygen for the oxidation of amines to amides are considered
as green and sustainable oxidants. Due to the fact that, oxygen
from air is an ideal source for the oxidation transformations
and is abundantly available in nature and also environmentally
friendly as it generates water as a co-product. Recently we
disclosed the oxidation of benzyl amines into corresponding
amides and employed excess amount of oxidising agent TBHP
(Scheme 1).9 However, our reported method is an efficient,
but it needs more than stoichiometric use of TBHP. In
continuation of our efforts and to overcome the drawbacks of
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine
Chemicals Research Institute, G. B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
E-mail: adimurthy@csmcri.res.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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the above methods on amide synthesis, we report herein a conditions, the reaction was performed without VsioewlvAertnictle, O6n2lin%e
DOI: 10.1039/C8GC03726D
yield of desired benzamide 2a was isolated after 12h (entry 3).
benign and
sustainable method for the selective oxidation of benzyl Further, when the reaction was conducted in open air instead
amines to amides utilising atmospheric oxygen as a source of of closed cap without any solvent, 2a was obtained in 82%
oxidant and ionic liquid as a catalyst under metal-free yield (entry 4). The same experiment was performed under
conditions.
oxygen atmosphere (balloon), the yield of desired product 2a
Based on our previous results10 and careful survey of the was decreased to 72% (entry 5). In this case the formation of
literature reports our attention has been drawn to employ corresponding benzenemethanamine (benzylamine) formation
inexpensive and readily available catalysts on amide synthesis. was observed along with 2a. The reaction of benzylamines
Selective oxidation reactions using ionic liquids (ILs) play an under oxygen atmosphere, the imine formations were
important role from the environmental and green chemistry reported.14 To check the role of oxygen, in the present
point of view. Due to their unique physical properties such as transformation,
a reaction was performed under inert
the non-volatility, thermal stability, non-explosion, high atmosphere, reaction was completely ceased (entry 6). Hence,
polarity, and temperature-dependent miscibility with water. the aerobic oxidation of 1a to 2a is more favourable under the
Hence ILs attracted considerable attention and are considered present conditions (entry 4).
as green alternatives to volatile organic solvents and as Further we screened different ionic liquid catalysts such as
catalysts.11,12 Recently, Bu4NOH (aqueous) and 1-Benzyl-3- (Pr)4NOH,
ethylammoniumnitrate
(EAN)
and
2-
methylimidazolium
bis(trifluoromethylsulfonyl)imide hydroxyethylammoniumformate (OH-EAF) under the same
([BnMIm][NTf2], have been employed for the aerobic oxidative
Table 2. Substrate scope of various benzylaminesa
O
Table 1: Optimisation of reaction conditionsa
(Bu)4NOH
NH2
O
Ar/
Het
NH2
(15 mol %)
Air
Ar/
Het
Aerial O2
NH2
NH2
2a
1a
1
2
O
O
O
O
Catalyst
(mol%)
Solvent
(1mL)
Temp
(°C)
Yield
(%)
S.No.
NH2
NH2
NH2
NH2
2c,
O
75%
MeO
2d,
O
80%
1b
2b
DCE
ACN
70
70
0
0
F
(Bu)4NOH (30)
(Bu)4NOH (30)
2b,
84%
2a,
95%
O
O
NH2
NH2
3b
70
62
(Bu)4NOH (30)
NH2
NH2
2h,
O
89%
F3C
2g,
43%
O2N
2f,
49%
Cl
4
(Bu)4NOH (30)
(Bu)4NOH (30)
70
70
82
72
2e,
71%
5c
Cl
O
OMe O
F
O
6d
7
(Bu)4NOH (30)
(Pr)4NOH (30)
EAN
70
70
70
0
NH2
NH2
NH2
NH2
nd
nr
2l,
50%
2k,
64%
2j,
O
53%
2i,
O
85%
Cl
8
O
NO2
O
9
10
11
12
13
14
15
16e
17e
OH-EAF
70
70
70
70
rt
nr
83
96
72
22
75
84
74
86
O
NH2
NH2
NH2
(Bu)4NOH (20)
(Bu)4NOH (15)
(Bu)4NOH (7.5)
(Bu)4NOH (15)
(Bu)4NOH (15)
(Bu)4NOH (15)
(Bu)4NOH (15)
(Bu)4NOH (15)
H2N
NH2
O
2m,
83%
2n,
O
40%
2o,
2p,
95%
85%
OMe
NH2
O
O
O
O
S
O
NH2
NH2
60
80
70
70
NH2
N
2r,
NH2
71%
NH2
49%
N
2s,
74%
2t,
80%
2u,
2q,
72%
aReaction condition: all reactions are performed using 1.0 mmol of
1, in open air, 70°C, for 12 h, isolated yields.
aConditions: 1a (1.0 mmol), solvent, catalyst, under open air,
conditions, but no product formation was observed (Table 1,
entries 7-9). We then performed the reaction by decreasing
the catalyst (Bu4NOH) loading to 20 mol% and 15 mol%, in the
former case the yield of 2a was decreased to 83% (entry 10)
and
in later case the yield was increased to 96% at 70 ℃ for 12
hours (entry 11). However, further decrease of catalyst load to
7.5%,
the yield of 2a was dropped to 72% (entry 12). Reactions
performed either with lowering of reaction temperature
(entries 13–15) or time (entries 16 &17) the yield of 2a was
reduced.
b
c
d
12 h, isolated yiels. Closed tube, Oxygen (balloon). Nitrogen
atmosphere. eReaction time 6 & 10 h in entries 16 and 17.
degradation of lignin to obtain oxygenated low molecular
weight organic molecules.13 In this context, we envisioned our
studies on selective benzylic oxidation of benzylamine 1a to
benzamide 2a (Table 1). Initially benzylamine 1a was subjected
using 30 mol% of Bu4NOH (aqueous) in dichloroethane DCE as
solvent in screw capped tube at 70 ℃ for 12 h reaction time,
no desired product formation was observed (Table 1, entry 1).
Both in DCE and acetonitrile as solvent we didn’t observe, the
desired benzamide 2a formation (entry 1 & 2). Under the same
2 | J. Name., 2012, 00, 1-3
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On the basis of the results obtained, the optimized conditions when we subjected the benzyl amine 1 to the optimised
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were set as 15 mol% of ionic liquid catalyst (Bu4NOH), under conditions of table 2, using elemental suDlfOurI:,1t0h.1e03p9r/oCd8uGcCt0N37-26D
aerobic oxidative conditions at 70 ℃ for 12 hours reaction
An-Xin Wua Gruop,
56
5843-5846.
Tetrahedron Letters, 2015,
time for the present transformation. As listed in Table 2, the
oxidative amidation of benzylic amines 1 was found to afford
the various amides 2 in moderate to good yields under aerobic
mild oxidative conditions. We examined the oxidation of para
substituted benzylamines having electron-rich and electron-
deficient groups, these substrates proceeded smoothly under
the optimized conditions to give selectively the corresponding
benzamides 2b–2g in good yields (43–84 %). The substrates
having strong electron withdrawing groups (-NO2, and -CF3),
moderate yields (49% and 43%) of products 2f and 2g were
observed. The presence of both electron-donating groups
(methyl and methoxy) and electron-withdrawing groups
(bromo, chloro, fluoro, nitro) either at ortho or meta position
of benzyl amines were tolerated in the reaction and smoothly
to afford the corresponding benzamides 2h–2n in moderate to
good yields (40–89 %). In the case of ortho nitro derivative 2n,
comparatively low yield (40%) was observed may be due to
both electron withdrawing effect as well as some steric
hindrance. In case of 1,3-phenylenedimethanamine and 1,4-
phenylenedimethanamine both methylene groups undergo
aerobic oxidation procedure and provided the corresponding
products 2o and 2p 85% and 95% yields respectively. It is
noteworthy to mention here that, the products
isophthalamide 2o terephthalamide 2p were obtained in good
and excellent yields in the pure form (by NMR) without
separation by column chromatography, but by simple
extraction and removal of solvent. The molecule
terephthalamide is an important starting material in polymer
industry.15 The pyrene methylamine gave the pyrene-1-
carboxamide 2q in 49% yield. The present conditions were also
amenable to hetero primary amines like pyridin-2-
Path I
Ar
NH2
Ar CHO
+
Path II
S
I2
NaSH
R
R
Ar
N
Ar
N
H
Ar
NH2
Path III
R
Ar
N
H
Savateev Group,
,
20
Green Chem. 2018, , 838–842
S
light irradiation
K-PHI
N
NH2
S8
H
+
Solvent, 70 °C
Present approach
ionic liquid
S
S
N
NH2
NH2
Ar/
Het
Ar/
Het
catalysed
Ar/
Ar/
Het
H
Het
3'
S8
3
not observed
Solvent Free, Oxidant free
Scheme 2. Synthetic approach of Thioamides
benzylbenzothioamide
3
was obtained instead of 3’
benzothioamide (Scheme 2). Further, to get different
Table 3. Substrate Scope for thiobenzamides with elemental
sulfura
S
S
(Bu)4NOH
(15 mol %)
NH2
3'
not observed
NH2
N
H
Ar/
Ar/
Ar/
Ar/
S8
Het
Het
+
Het
Het
Air
1
3
S
S
S
N
H
MeO
Cl
OMe
Cl
N
N
H
ylmethanamine,
ylmethanamine
pyridin-3-ylmethanamine,
and thiophen-2-ylmethanamine
furan-2-
and
H
3a, 70%
3b, 79%
Cl
3c, 70%
S
S
successfully provided corresponding heteroamides 2r–2u in
moderate to good yields. Unfortunately, this protocol is not
applicable to aliphatic amines as well as in secondary and
tertiary amines respectively.
S
Cl
N
H
N
H
N
H
MeO
OMe
3d, 83%
3f, 57%
S
3e, 58%
S
S
F
F
As the handful of benzamides were obtained under mild
metal-free conditions, we thought of extending the same
conditions to thioamides synthesis. In this context, when we
searched the literature on thioamides synthesis, recently
Savateev’s group16 has been reported the oxidative
thioamidation of benzylamine to N-benzylbenzothioamide
using potassium poly(heptazine imide), K-PHI as photo catalyst
(Scheme 2). As highlighted by Savateev on the synthesis of
thioamides, the most conventional methods are through the
Lawesson reagents17 and Willgerodt–Kindler reactions.18
Although, these methods are efficient, the development of
convenient and practical method for synthesis
of thioamides under transition metal-free, inexpensive and
catalytic conditions still holds its relevance, hence it is a highly
desirable and yet to be a challenging task. From the viewpoint
of green chemistry, it is desirable to develop operationally
simple and environmentally benign conditions. To this end,
N
N
H
N
H
H
Cl
Cl
F
F
3i, 61%
3g, 61%
3h, 52%
S
S
S
N
N
NH
N
H
S
N
S
H
F3C
CF3
3j, 66%
3k, 35%
3l, 75%
aReaction condition: all reactions are performed at 1.0 mmol
of amines, 0.5 mmol S8 in open air, 70° C, for 12h, isolated
yields.
benzylbenzothioamides the same conditions were applied with
different
benzylamines
and
corresponding
N-
benzylbenzothioamides 3a–3i were obtained in good yields
(57-83%), with both electron donating (Me, OMe) and electron
withdrawing groups. It is noteworthy to mention that, under
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these conditions the products N-(pyridin-2-ylmethyl)pyridine- may proceed via radical pathway. Further, to know the
View Article Online
DOI: 10.1039/C8GC03726D
2-
reaction intermediate,
NH2
carbothioamide 3j and N-(thiophen-2-ylmethyl)thiophene-2-
carbothioamide 3k were obtained in 35% and 75% yields
respectively. While the yields of these products are low, they
exemplify the ability to expand the method towards the
different heteroamides as well as thioamides.
O
NH2
Optimised
Conditions
NH2
eq. 1
eq. 2
TEMPO/
BHT
N
O
1a,
1.0 mmol
1.2 equiv.
2a
, 0%
detected by HRMS
O
Optimised
Conditions
N
NH2
Table 4. Ionic liquid catalysed benzylic oxidationa
2a
, 0%
6
, 1.0 mmol
S8
S
Optimised
Conditions
1a
TEMPO/
BHT
eq. 3
O
N
H
(Bu)4NOH
Ar/
(15 mol %)
Air
Ar/
1.0 equiv. 1.0 equiv.
1.5 equiv.
Het
Het
3a
, 60%
4
5
Optimised
Conditions
eq. 4
eq. 5
S8
6
3a
O
O
O
O
99%
1.0 mmol
0.5 mmol
N
S
O
1a
S
-NH3
5c, 33%
5d, 83%
5a, 81%
5b, 75%
N
H
NH2
aReaction condition: all reactions are performed using 1.0
mmol of 4, in open air, 70°C, for 12 h, isolated yields.
3a;
52%
7
Scheme 4. Control experiments
To further ascertain the scope of the present method on
selective benzylic oxidation, we subjected the important but
representative benzylic substrates 4 (Table 4). Under the
optimised conditions of table 2, diphenylmethane, 2-
benzylpyridine and 1,2-diphenylethan-1-one gave the
corresponding oxidised products benzophenone 5a,
phenyl(pyridin-2-yl)methanone 5b, benzyl 5c, in 81%, 75% and
33% yields respectively. The cyclic benzylic derivative such as
9H-fluorene was also underwent to this procedure and afford
the oxidised product 9H-fluoren-9-one (5d) in 83% yield.
(E)-N-benzyl-1-phenylmethanimine 6 was subjected to the
optimised conditions, 2a formation was not observed (Scheme
4, eq.2). It gives an idea that, the reaction does not proceed
through the imine intermediate. To understand the reaction
pathway for benzylbenzothioamides (Table 3), the reaction of
1a and elemental sulfur was conducted by the addition of
TEMPO and BHT, under these conditions the desired product
3a was obtained in 60% yield (Scheme 4, eq. 3). This reaction
indicates that, unlike benzamides, thiobenzamides may not go
through the radical path, but it may proceed through ionic
pathway. When 6 was subjected to the optimised conditions
along with elemental sulfur, quantitative yield of 3a was
obtained (Scheme 4, eq. 4). Further, benzothioamide 7, was
reacted with 1a, it afford 52% yield of desired thioamide 3a,
through transthioamidation20 mechanism (Scheme 4, eq. 5).
O
NH2
O
NH2
O
O
H2N
NH2
N
2a;
2p;
10 mmol,
(1.50g), 91%
2s;
10 mmol,
10 mmol
(0.998g), 82%
(0.762 g), 68%
The results of equations
4 and 5, suggest that, the
S
thioamidation reaction may procced through the imine as well
as benzothioamide intermediates.
O
NH
NH2
3a;
5a;
10 mmol
(1.415 g), 62%
10 mmol
O
NH2
2a
(1.274 g), 70%)
NH2
1a
Scheme 3. Gram scale synthesis of benzylic oxidative products
A
Bu4NOH
(IL)
OH
OH
To gain insight into the reaction mechanism, some control
experiments were performed (Scheme 4). Initially, the reaction
of 1a was conducted by the addition of radical scavengers
TEMPO and BHT under optimized conditions to know whether
the reaction proceeds via radical or ionic path (Scheme 4, eq.
1). In both cases, no desired benzamide 2a formation was
observed
OH
SET
O2
H2O
O2
NH2
NH2
O
O
C
B
Scheme 5. Plausible mechanism for 2a
under these conditions. TEMPO adduct formation was
observed by HRMS analysis.19 It indicates that the reaction
Based on the control experiments and related precedents,21
plausible reaction mechanism has been proposed (Scheme 5).
Initially, Bu4NOH reacts with atmospheric oxygen generates
a
4 | J. Name., 2012, 00, 1-3
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hydroxyl radical (OH•) and superoxide radical (O2−•).22a Further, present strategy represents
we recorded EPR spectra of reaction mixture in acetonitrile at development in synthetic chemistry.
160°C temperature and we observed singlet with g-factor
COMMUNICATION
a
green andViewsAigrtincliefiOcnalinnet
DOI: 10.1039/C8GC03726D
2.0124 at 334 mT magnetic field (for EPR spectra see SI). This
may indicate the generation of superoxide radicals (O2−•) as
reported in the literature.22b,c The hydroxyl radical reacts with
benzylamine 1a and give a complex of ammonium cation
radical A through single electron transfer23 which undergo
deprotonation in presence of catalyst and generates benzylic
radical intermediate B. Intermediate B reacts with superoxide
radicals (O2−•) generates α-peroxo intermediate C,24 and its
subsequent oxidation yield the desired benzamide 2a (Scheme
5). The thioamide formation may proceed by two possible
pathways (Scheme 6). Initially, aerobic
Conflicts of interest
There are no conflicts to declare.
Acknowledgement
CSIR-CSMCRI Communication No. 193/2018. We are thankful
to “Analytical Discipline and Centralized Instrumental
Facilities” for instrumentation facilities. A.J., R.K. and R.S. are
thankful to CSIR, UGC, DST (Inspire) for their fellowships. We
thank DST, New Delhi (EMR/2016/000010) for the research
grants and CSIR-CSMCRI (OLP-0088 and MLP-0027) for the
partial financial support.
NH
Bu
Bu
Bu
S
7
N
OH
IL
Bu
3a
S
1a
NH2
O2
path-a
A
1a
NH3
H2O
path-b
Notes and references
NH3
Bu
Bu
Bu
Bu
Bu
Bu
Bu
N
N
1. E. Valeur and M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631.
2. (a) Wieland, T.; Bodanszky, M. The World of Peptides: A Brief
History of Peptide Chemistry; (b) Springer, 1991.C. E.
Mabermann in Encyclopedia of Chemical Technology, Vol. 1
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Kroschwitz), Wiley, New York, 1991, 346 – 356; (e) R. C. Larock,
Comprehensive Organic Transformations, 2nd ed., Wiley-VCH,
New York, 1999.
N
S
OH
Bu
6
H
S
NH2
NH
Ph
S
HN
Ph
1a
B
NH2
S
N
C
H
3a
Scheme 6. Plausible reaction mechanism for 3a
oxidation of 1a generates imine intermediate A in the
presence of Bu4NOH.25 Reaction of this intermediate A with 3. (a) X. Liu, C. Chi Hsiao, L. Guo and M. Rueping, Org. Lett.,
2018, 20, 2976−2979; (b) D. Yu Wang, M. Kawahata, Ze-Kun
Yang, K. Miyamoto, S. Komagawa, K. Yamaguchi, C. Wang and
M. Uchiyama, Nature Chemistry, 2016, 8 75-79; (c) G. Meng
and M. Szostak, Org. Lett., 2018, 20, 6789–6793.
4. (a) C. L. Allen, R. A. Chhatwal and J. M. J. Williams, Chem.
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In conclusion, we have developed a novel ionic liquid catalysed
aerobic oxidation of benzyl amines to benzamides under
metal-free conditions. It is noteworthy to mention that, the
present method is not only base-free and solvent-free
conditions, but utilised atmospheric oxygen as a sole oxidant.
Under the same conditions with elemental sulfur,
corresponding benzylbenzothioamides were obtained from
benzyl
amines.
Under
the
optimised
conditions
benzophenone, phenyl(pyridin-2-yl)methanone, benzyl, 9H-
fluoren-9-one and 1H-inden-1-one were obtained. The mild
reaction conditions, metal-free, base-free and solvent-free
conditions good functional-group tolerance, broad range of
products (amides, thioamides, and benzylic) and applicability
at gram scale for practical synthesis of desired amides, the
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DOI: 10.1039/C8GC03726D
S
O
Ionic liquid
S8
Ar/
Het
Ar/
Het
Ar/
Het
Ar/
Het
N
Ionic liquid
NH2
H
NH2
O2
O
Ionic liquid
O2
Metal
Solvent
Oxidant
Base
37 examples
up to 95% yield
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